Retinal Ganglion Cell Interactions Shape the Developing Mammalian Visual System Shane D’Souza1,2,3,* and Richard A

REVIEW Retinal ganglion cell interactions shape the developing mammalian visual system Shane D’Souza1,2,3,* and Richard A. Lang1,2,4,5

ABSTRACT Unraveling how visual processes take place requires an understanding Retinal ganglion cells (RGCs) serve as a crucial communication of the cell diversity, mapping their connections, deciphering channel from the retina to the brain. In the adult, these cells receive communication patterns and determining how each cell is generated. input from defined sets of presynaptic partners and communicate with In addition, it is vital to determine how transient developmental postsynaptic brain regions to convey features of the visual scene. interactions between cells shape the visual system. By systematically However, in the developing visual system, RGC interactions extend addressing these various aspects of the visual system, we can slowly beyond their synaptic partners such that they guide development begin to tease apart the complexities of visual mechanisms. before the onset of vision. In this Review, we summarize our current RGCs, the sole projection neurons of the retina, have been well- understanding of how interactions between RGCs and their studied for their diversity, connections, signaling and development. environment influence cellular targeting, migration and circuit Between electrophysiological profiling and single-cell transcriptomics, maturation during visual system development. We describe the roles this class can be further divided into 30-46 distinct types in mice (Baden of RGC subclasses in shaping unique developmental responses within et al., 2016; Tran et al., 2019). Each RGC type optimally encodes the retina and at central targets. Finally, we highlight the utility of RNA unique features of the visual scene (contrast, motion, color, etc.), and ‘ ’ sequencing and genetic tools in uncovering RGC type-specific roles projects to diverse central targets in the brain that decode each feature during the development of the visual system. (Dhande et al., 2015). Some RGC types express the photopigment melanopsin (Opn4), conferring them with direct photosensitivity KEY WORDS: Retinal ganglion cells, Visual system, (Berson et al., 2002; Hattar et al., 2002). Collectively, these multiple Non-autonomous, IpRGCs, Cell-cell interactions, Retina photosensitive RGCs are referred to as intrinsically photosensitive RGCs (ipRGCs) and make up a subclass representing six unique RGC Introduction types (M1-M6; reviewed by Sondereker et al., 2020). The retina serves as the visual gateway to the world around us. This Interestingly, RGCs also represent one of the first cell classes light-sensitive neural tissue is located in the posterior of the eye generated during retinal development (Fig. 1B) (Young, 1985) and (Fig. 1A) and has evolved to detect photons, extract visual features and their cellular diversity is established by postnatal day (P) 5 (Rheaume convey this information to the rest of the brain (Baden et al., 2020). et al., 2018; Tran et al., 2019), before eye opening in mice. Their Together, the eye and all brain regions involved in processing retinal numerous interaction partners in the brain and retina, in addition input form the visual system (Seabrook et al., 2017). Through the to their early generation, indicate that RGCs could regulate complex and integrated function of multiple cell classes in the retina developmental events along the visual pathway. Over the last two (Fig. 1A), we are capable of sensing, experiencing and responding to decades, evidence has emerged indicating that RGCs function as more visual scenes that range from subtle and static to vivid and dynamic. than visual feature detectors and information conduits. Although Photoreceptors (rods and cones) express photopigment proteins and sparse (∼2.7% of all retinal cells) (Young, 1985), RGCs serve as a detect light. These photoreceptors signal to bipolar interneurons, developmental nexus for the visual system. By interacting with which then provide excitatory input to retinal ganglion cells (RGCs) migrating retinal neurons, retinal and vascular progenitors, astrocytes (Fig. 1A). Horizontal cells provide inhibitory input to photoreceptors, and central targets, they influence the course of visual system whereas amacrine cells inhibit RGCs and bipolar cells (Masland, development, well before the visual experience. 2012). RGCs have axons that extend through the optic nerve and In this Review, we provide an overview of the evidence suggesting convey information from the retina to numerous targets in the brain – that RGCs play a developmental role in mammalian visual system shaping not only visual perception, but also our physiology and development. When applicable, we describe key concepts gleaned circadian behavior (Schmidt et al., 2011; Baden et al., 2020). from non-mammalian vertebrate models. We describe how early RGC activity, structure and secreted factors establish structural, 1The Visual Systems Group, Cincinnati Children’s Hospital, Cincinnati, OH 45229, molecular and physiological properties within the visual system. USA. 2Center for Chronobiology, Abrahamson Pediatric Eye Institute, Division of When available, we highlight data that implicate particular RGC Pediatric Ophthalmology, Cincinnati Children’s Hospital, Cincinnati, OH 45229, subclasses (e.g. ipRGCs) as modulators of retinal and central USA. 3Molecular and Developmental Biology Graduate Program, University of Cincinnati, College of Medicine, Cincinnati, OH 45229, USA. 4Division of development, and how this influences behavior. Finally, we Developmental Biology, Cincinnati Children’s Hospital, Cincinnati, OH 45229, USA. describe how next-generation tools (bioinformatics and genetics) 5Department of Ophthalmology, University of Cincinnati, College of Medicine, can be applied towards understanding how RGCs contribute to Cincinnati, OH 45229, USA. development of the retina, brain and mammalian behavior. *Author for correspondence ([email protected]) The roles of RGCs in retinal development S.D., 0000-0001-6344-1434 The developmental influence of RGCs can be categorized into two This is an Open Access article distributed under the terms of the Creative Commons Attribution types: activity-dependent input (in which RGCs depolarize and License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. release neurotransmitters) and activity-independent input (secreted DEVELOPMENT

1 REVIEW Development (2020) 147, dev196535. doi:10.1242/dev.196535

A Retina organization B Retinal neuron glia generation C Intra-retinal RGC signaling

OS/IS

ONL Shh OPL Cell proportion Cell Gdf11 Vegf INL Shh IPL Pdgfa GCL E10 P10 Developmental age

Key

Rod Cone Horizontal cell Bipolar cell Amacrine cell RGC Müller glia RPC Astrocyte Vasculature

Fig. 1. Retinal architecture, cell generation and intra-retinal signaling during retinal development. (A) The mammalian neural retina highlighting photoreceptors (rods, cones), interneurons (horizontal cells, bipolar cells and amacrine cells), projection neurons (RGCs), Müller glia and retinal progenitor cells (RPC) structured into three nuclear/cellular layers (ONL, outer nuclear layer; INL, inner nuclear layer; GCL, ganglion cell layer) and two neuropils (OPL, outer plexiform layer; IPL, inner plexiform layer). (B) Developmental generation of mouse retinal cell types (based on Young, 1985) depicting both the sequence of generation and relative proportion of each cell type. (C) Interactions between immature RGCs and other developing cell types in the context of retinal development. Arrows depict RGC-derived factors described in the text. OS/IS, outer segment/inner segment of photoreceptor cells. factors or structural aspects of the cell). In this section, we describe (Shh) was found to be expressed by developing RGCs, while its how these forms of early ‘RGC input’ influence the developing cognate receptor (patched) is expressed by RPCs (Jensen and retina, optic tract and optic chiasm (Fig. 1C). Wallace, 1997; Zhang and Yang, 2001). These discoveries position this axis as a feedback pathway that titrates RGC production in the RGC-derived factors modulate progenitor proliferation and retina. More recent studies have firmly established a developmental differentiation role for RGC-derived Shh. Murine Shh is initially expressed by The neural retina (Fig. 1A) is derived from a pool of multipotent RGCs of the central retina at embryonic day (E) 12 (Wang et al., retinal progenitor cells (RPCs). These cells give rise to all retinal 2005). In fish and mice, Shh expression expands in a central-to- neurons and Müller glia, largely relying on intrinsic regulation (such peripheral wave that closely mirrors, but lags behind, the wave of as transcriptional regulators and chromatin state) and extrinsic cues RGC generation (Neumann and Nuesslein-Volhard, 2000; Wang (paracrine factors) to guide specification into one of seven post- et al., 2005). RGC-derived Shh serves two major roles during retinal mitotic cell classes (Cepko, 2014). Two models of intrinsic regulation development: promoting proliferation of RPCs, and simultaneously have been proposed to describe how progenitors generate each of these suppressing RGC generation. Loss of Shh in the peripheral retina classes in a temporally defined sequence (Fig. 1B). The deterministic leads to reduced RPC proliferation, increased RGC production, and model suggests that intrinsically different RPCs are competent to failure of later-born cells to be generated (Wang et al., 2005). generate specific groups of classes (Turner et al., 1990; Trimarchi Another diffusible factor, vascular endothelial growth factor et al., 2008). By contrast, the stochastic model suggests that RPCs are (Vegf), is expressed by RGCs, and its receptor (Flk1; also known equipotent and, through a probabilistic process, generate cell classes as Kdr) is expressed by endothelial cells (Yamaguchi et al., 1993) and in the quantities and order observed during retinal development RPCs (Yang and Cepko, 1996). This expression pattern is conserved (Cayouette et al., 2003; Gomes et al., 2011; He et al., 2012). Our in chicken, in which secreted Vegf suppresses RGC-genesis and current understanding, however, suggests that both modalities of promotes RPC proliferation, reminiscent of Shh function in the development likely occur in the retina (Cepko, 2014). In addition to developing retina (Hashimoto et al., 2006). RGC-specific ablation differentiation of these classes, RPCs must also self-renew to generate experiments (Mu et al., 2005), and mice with RGC loss (Gan et al., cells in appropriate quantities. Although intrinsic factors appear to be a 1996; Brown et al., 2001), also complement the claim that RGCs are a major driver of clone size (and thus number of RPC-derived retinal source of proliferative cues. By contrast, not all RGC-released factors cells) (He et al., 2012), there are documented circumstances in which influence RPC proliferation. RGC-derived growth differentiation RGC-derived signals (extrinsic cues) shape the generation of specific factor 11 (Gdf11) inhibits progenitors from adopting the RGC fate cell classes and cell quantity during development. without altering cell cycle dynamics. Instead, it is thought that Gdf11 Early experimental approaches using dissociated or explanted temporally restricts the expression of key RGC-competence factors rodent retina cultures, heterochronic mixing (combining cells of (Kim et al., 2005). The gene encoding one such transcription factor, different developmental ages) and media supplementation suggest Atoh7, has been extensively studied for its requirement in RGC- that post-mitotic cells have the capacity to influence RPC genesis through the induction of an RGC-fate transcriptional program differentiation (Watanabe and Raff, 1990, 1992; Altshuler and (Liu et al., 2001; Wu et al., 2015). In several vertebrate classes Cepko, 1992; Waid and McLoon, 1998). The presence of RGCs (in assessed (Brown et al., 2001; Kay et al., 2001; Liu et al., 2001), culture) prevents progenitors from adopting the RGC fate (Waid and including humans (Prasov et al., 2012), mutations in Atoh7 or its McLoon, 1998), and the responsible RGC factor(s) appears to be regulatory elements lead to an almost complete loss of RGCs, with diffusible as opposed to juxtacrine. The morphogen sonic hedgehog additional pathologies associated with the eye (Ghiasvand et al., DEVELOPMENT

2 REVIEW Development (2020) 147, dev196535. doi:10.1242/dev.196535

2011; Prasov et al., 2012; Kondo et al., 2016; Atac et al., 2019). In interaction between multiple cell types, RGCs do not appear to be a addition, recent data suggest that Atoh7+ lineage RGCs non- major influence during construction of the IPL. Further research autonomously promote the survival or generation of Atoh7− into specific circuits and RGC types will help determine the role of lineage RGC types (Brodie-Kommit et al., 2020 preprint). Thus, RGCs in synaptic lamination. RGCs appear to regulate their own production by feeding into RPC Interestingly, one type of RGC, the M1 ipRGC, extends its transcriptional programs via paracrine signaling. dendrites beyond the IPL during development, and is poised to Although it is clear that RGCs enhance progenitor proliferation regulate more than just its synaptic partners. ipRGC types are through secreted factors, it is debated whether the RGC-to-RPC axis defined by their dendritic structure and lamination pattern, soma influences fate determination. Studies involving gene deletions of key size, melanopsin expression and projections to central retinal targets factors in RGC development and production [Shh, Atoh7, Brn3b (Sondereker et al., 2020). M1 ipRGCs terminate their dendrites in (Pou4f2), etc.] argue that the RGC-to-RPC signaling axis, in addition the outer IPL (Provencio et al., 2002), but during postnatal to regulating proliferation, differentially influences the production development, they extend their dendrites towards the outer retina and survival of certain cell classes (Wang et al., 2002, 2005; Moshiri (Fig. 2B,C) making them ‘biplexiform cells’ (Renna et al., 2015). et al., 2008; Bai et al., 2014). Studies using intersectional genetics to These atypical projections, termed outer retinal dendrites (ORDs), specifically ablate RGCs (Six3-cre; Brn3bz-DTA)suggestthatallnon- are transient and their distribution is limited to the dorsal retina RGC cell classes are produced in correct proportions but, overall, (Sondereker et al., 2017). The close proximity of these dendrites to retinal cell number is greatly reduced (Mu et al., 2005). However, cone terminals suggests a potential interaction between these two both forms of manipulation have limitations that make it difficult to classes of photoreceptor. Indeed, early activity of murine ipRGCs is interpret their meaning for fate-determination. For example, Shh necessary to restrict cone photoreceptors to the outer retina (Tufford expression is not restricted to RGCs during development – murine et al., 2018). This occurs through an indirect mechanism: ipRGC amacrine cells and cones also express Shh at later developmental ORDs contact dendrites of dopaminergic amacrine cells (DACs) stages (Jadhav et al., 2006). Thus, alterations in germline Shh and through potential regulation of dopamine release, cones are knockouts may reflect alternative sources of Shh. In addition, the restricted to their appropriate layers (Fig. 2D). In addition, cone cell kinetics of RGC death in the Six3-cre; Brn3bz-DTA line is not fully bodies are further restricted to the apical aspect of the outer nuclear understood, making it possible that transient RGCs are sufficient to layer (ONL) via light- and activity-independent input of ipRGCs shape fate determination. Further work is required to establish RGCs (Fig. 1A; Tufford et al., 2018). Taken together, these studies suggest as bona fide modulators of fate determination in the retina. that, as a class, RGCs do not shape their local synaptic plexus (i.e. the IPL), but signaling of an RGC subclass (ipRGCs) restricts Non-autonomous regulation of lamination via RGCs non-synaptic partners to their appropriate location. During development, retinal neurons must be generated in the appropriate numbers, but must also locate their synaptic partners in Developing astrocyte and vascular networks require immature order to effectively encode the visual scene. In the first few postnatal RGC input weeks, the processes of synaptic formation, pruning and circuit RGC-mediated regulation of visual development is not limited to establishment occur through cellular activity (Demarque et al., 2002; neuronal cells of the retina (Fig. 2A). As RGCs are generated, their Goldberg et al., 2002), expression of attractive or repulsive cell- axons project towards the optic disc (Fig. 2B,E), fasciculate to form surface proteins (Sanes and Zipursky, 2010; Missaire and Hindges, the optic nerve, and travel great distances to contact central targets. At 2015; Sanes and Zipursky, 2020), and release of neurotransmitters the optic disc, RGCs are poised to interact with cells of the optic stalk, (Morgan et al., 2008; Kerschensteiner et al., 2009; Blankenship and astrocytes and the hyaloid vasculature – a transient structure that Feller, 2010). In particular, these events take place in the inner serves as the primary nutrient source for the developing eye (Fig. 2E). plexiform layer (IPL) (Fig. 1A), a synaptic ‘highway’ in which Cues originating from developing RGC axons appear to stimulate bipolar axons meet RGC and amacrine dendrites in distinct laminar proliferation of astrocyte precursors (Burne and Raff, 1997). sublayers. Here, the visual field is preprocessed by the retina and Surprisingly, in addition to its local role in the neural retina, RGC- separated into parallel channels based on information content, before derived Shh is transported down the axon and promotes astrocyte being conveyed to the brain (Sanes and Zipursky, 2010, 2020). precursor and optic stalk progenitor proliferation in the optic disc IPL laminar structure is generated via attractive interactions (Fig. 2E,F; Wallace and Raff, 1999; Dakubo et al., 2003). Overall, between presynaptic and postsynaptic cells (Yamagata et al., 2002; RGC-derived Shh serves similar roles across the developing visual Yamagata and Sanes, 2008). Given the early generation, migration system, promoting proliferation of retinal, astrocyte and optic stalk and activity of RGCs (Young, 1985) (Fig. 2A), one might expect progenitor cells. RGCs to guide axonal and dendritic lamination of the later-born Astrocytes enter the retina through the optic disc, migrate radially bipolar and amacrine classes (Fig. 1B). There is some evidence for and provide a framework for endothelial cell growth and vascular this in the zebrafish retina, in which RGCs are transiently required development (Fruttiger, 2007; Sun and Smith, 2018). Radial for appropriate amacrine dendrite lamination in the IPL (Kay et al., migration of astrocytes depends on paracrine signaling and 2004). In mice, as we have discussed, studies using genetic ablation structural components of RGCs: platelet derived growth factor or loss of RGCs reveal that ganglion cells may not be required for alpha (Pdgfa) and the RGC axon itself. RGC-derived Pdgfa binds to general targeting or lamination of neuronal processes in the its receptor (Pdgfra) on astrocytes and serves as a mitogen and mammalian IPL (Mu et al., 2005; Moshiri et al., 2008). It is chemoattractant (Fruttiger et al., 1996; Tao and Zhang, 2016), possible that, within a circuit, interacting inner retinal neurons facilitating migration towards the peripheral retina. While on their mutually restrict lamination patterns. For example, the ramification migratory route, astrocytes closely associate with RGC axons and are of ON-OFF direction-selective RGC dendrites is dependent on the believed to use them as a pre-existing scaffold for motility and spatial homophilic interaction between cadherins expressed by these cells patterning. In the retina of mice that lack RGCs (Atoh7 knockouts) or and their synaptic partners, the starburst amacrine cells (SACs) have RGC axon defects (RGC-specific Robo1/2 mutants), retinal

(Duan et al., 2018). Although it is clear that lamination requires the astrocytes display polarization defects, inappropriate migratory DEVELOPMENT

3 REVIEW Development (2020) 147, dev196535. doi:10.1242/dev.196535

A ~E12 P0 (birth) P7 P12 (eye opening) P30

Generation

RGC Activity

Inner plexiform Astrocyte migration

Superficial Intermediate Deep Vascular Hyaloid

BCD RGCs

Cone Drd4 & lamination OPL Cone terminals C, D

INL DAC M1 DAC Optic disc (dopamine)

IPL M1 (Glutamate?) GCL

RGCs Astrocytes E, F RGC axon Astrocytes EF Endothelial cells Axon (hyaloid artery) Light (through eyelid)

Immature astrocytes

M G1

Neural retina Neural Pdgfa

G2 S

Astrocyte precursors M G Astrocytes 1 Shh

RGCs Optic disc Optic Optic disc G2 S

Fig. 2. RGCs interact with non-synaptic partners to guide lamination and vascular development. (A) Timeline of retinal ganglion cell (RGC) generation and activity relative to development of the inner plexiform, migration of astrocytes and vascular growth/regression in the retina. (B) Whole-mount schematic representation of a developing retina depicting astrocyte migration from the optic disc. (C) Dendrites extending from M1 intrinsically photosensitive retinal ganglion cells (M1) and dopaminergic amacrine cells (DACs) extend beyond the appropriate synaptic location in the inner plexiform layer (IPL) towards the outer plexiform layer (OPL), where cone photoreceptor synaptic terminals are located. (D) Communication between the intrinsically photosensitive retinal ganglion cell (ipRGC) and DAC leads to dopamine release, activation of D4-type dopamine receptor (Drd4) on cones to restrict lamination of the cells to the outer nuclear layer (ONL). (E) Immature RGCs interact with migrating astrocytes and the hyaloid artery through RGC structure (axons) and RGC activity (photoreception), respectively. (F) Timeline of the influence of RGC-derived factors and structure on the glial/astrocyte lineage in the optic disc and to neural retina. GCL, ganglion cell layer; INL, inner nuclear layer. patterns and delayed vascular plexus formation (O’Sullivan et al., required for any form of astrocyte movement (Gnanaguru et al., 2013; 2017). Notably, physical RGC-astrocyte interactions are required Tao and Zhang, 2016). Thus, RGCs influence the astrocyte lineage – specifically for directional movement towards the peripheral retina, from generation to migration (Fig. 2E,F), and contribute to the whereas astrocyte-inner limiting membrane (ILM) interactions are development of the retinal vascular landscape. DEVELOPMENT

4 REVIEW Development (2020) 147, dev196535. doi:10.1242/dev.196535

Following astrocyte migration, endothelial cells are recruited forming brain regions (Fig. 3B; Wong, 1999; Firth et al., 2005; from the optic disc and migrate radially to form a superficial Huberman et al., 2008; Blankenship and Feller, 2010). As a retinal vascular plexus. From this initial plexus, endothelial cells reorient wave sweeps across the ganglion cell layer (GCL), neighboring their migration and expand towards the outer retina, forming the RGCs fire action potentials followed by a brief refractory period, in deep and intermediate plexus (Fig. 2A) (Sun and Smith, 2018). which a wave can no longer propagate. This information is received Beyond RGC-astrocyte interactions, immature retinal neuron by the visual thalamus and midbrain (McLaughlin et al., 2003; activity has also been associated with the development of these Ackman et al., 2012; Burbridge et al., 2014) and the competition of vascular plexuses (reviewed by Biswas et al., 2020). Spontaneous eye-specific wave activity drives refinement of contralateral and activity from retinal neurons, in the form of retinal waves ipsilateral projections (Fig. 3C,D). (Huberman et al., 2008), coincides with development of the RGCs do not passively participate in waves, but rather actively vascular networks (Weiner et al., 2019). Ablation or chemogenetic influence eye-specific segregation through diverse mechanisms. The inhibition of SACs prevents development of the deep plexus earliest forms of retinal waves (phase I waves) are thought to be (Weiner et al., 2019). On the other hand, ablating amacrine and propagated by connexin (Cx) gap-junction networks between horizontal cells severely reduces development of the intermediate dendrites of neighboring RGCs (Bansal et al., 2000; Syed et al., plexus (Usui et al., 2015). Although RGCs participate in retinal 2004) (Fig. 3B). The mechanisms that generate phase I waves are still waves, it has yet to be tested whether their wave-associated activity poorly understood; however, gap-junction propagation plays a role in has a direct effect on vascular development. However, experiments axon refinement at the dorsal lateral geniculate nucleus (dLGN) of the focused on RGC subclasses have hinted towards influence of RGC visual thalamus. Mice that lack gap-junction proteins Cx36 and Cx45 activity on vascular development. (Cx36/45 double knockout) do not display alterations in phase II or III ipRGCs express melanopsin as early as E15 in the mouse retinal waves, but have altered inter-wave firing patterns (Blankenship (McNeill et al., 2011), and are one of the earliest established et al., 2011). As a consequence, eye-specific projections in the dLGN photoreceptors in the neonatal retina (Sekaran et al., 2005; Kirkby are less segregated than wild-type or Cx45 knockout mice. Still, these and Feller, 2013; Caval-Holme et al., 2019). During vascular results warrant further investigation for two reasons. First, Cx36 and development, ipRGCs detect light and suppress angiogenesis, while Cx45 are both expressed in dLGN neurons, which are recipients of simultaneously promoting the timely regression of the hyaloid RGC input. Therefore, it is possible that defects observed in the Cx36/ artery (Rao et al., 2013). Visual deprivation (particularly during the 45 double knockout arise as a consequence of intrinsic changes at the fetal period in mice) or deleting melanopsin (Opn4 knockout mice) target rather than within the retina (Belluardo et al., 2000; Maxeiner leads to persistence of the hyaloid artery and overgrowth of the et al., 2003; Lee et al., 2010; Zlomuzica et al., 2010). Second, retinal vascular plexus. Elevated retinal neuron numbers in dark- amacrine and bipolar cells express Cx36/45 and may influence retinal reared or Opn4 knockout mice leads to a more hypoxic retina, waves independently of the RGC network (Mills et al., 2001; Han and increased retinal Vegfa production and feedback to the vascular Massey, 2005; Hansen et al., 2005). Targeted deletion of all detected compartment that expresses VEGF receptors (Vegfr2) (Rao et al., connexins from RGCs (Cx36, Cx45 and Cx30.2) will provide better 2013; Cristante et al., 2018). In addition, RGCs that express another insight into the role of inter-RGC gap-junctions in shaping retinal opsin, Opn5, indirectly regulate vascular development (Nguyen mapping (Völgyi et al., 2009; Müller et al., 2010; Akopian et al., et al., 2019). From P3-P8, Opn5-RGCs promote light-mediated 2014). reuptake of the neurotransmitter dopamine in the neural retina. This During development, ipRGCs also form gap-junction networks activity stabilizes the hyaloid artery by preventing the accumulation with neighboring ipRGCs and conventional RGCs (Kirkby and of dopamine in the vitreous, where it would act on D2 receptors Feller, 2013; Caval-Holme et al., 2019). Through these intra-retinal (Drd2) of endothelial cells to suppress the activity of Vegfr2 gap-junction circuits, ipRGCs increase their own sensitivity to light (Fig. 2E). Thus, the activity of opsin-expressing RGCs converges and simultaneously confer light-sensitivity to conventional RGCs on hyaloid artery regression, but acts through distinct mechanisms – (Caval-Holme et al., 2019). In the absence of phase II retinal waves one via a Vegfa-Vegfr2 pathway, and the other through a dopamine- (β2nAChR knockout and ChAT knockout mice), the retina D2-Vegfr2 pathway. In support of RGCs as regulators of hyaloid generates compensatory light-dependent waves that are driven by regression, loss of Atoh7 in mice and humans leads to persistence of these ipRGC circuits (Kirkby and Feller, 2013; Stacy et al., 2005). the hyaloid artery and failure of the retinal vasculature to effectively Initially, experiments implicated melanopsin-driven light responses develop (Ghiasvand et al., 2011; Edwards et al., 2012; Prasov et al., as modifiers of retinal waves and retinal mapping to the dLGN 2012). Together, the RGC population is a vital signaling and (Renna et al., 2011). More recent analysis, by contrast, suggests that, structural hub that establishes the framework for the development of although ipRGCs participate in phase II waves, their light- retinal astrocytes and vascular architecture. dependent activity does not modulate wave properties (Kirkby and Feller, 2013; Chew et al., 2017). M1 ipRGCs, however, appear Inter-RGC interactions in the developing visual system to be required physically for normal wave properties and maturation Thus far, we have discussed the various interactions between RGCs of the visual system. Ablation of M1 ipRGCs (Opn4DTA line) alters and other cell classes in the developing retina. However, RGCs also properties of phase II retinal waves, leading to failure of eye-specific interact with each other to guide their own development. RGC-to- segregation of retinal-dLGN projections (Chew et al., 2017). As M1 RGC interactions take place within the retina and at the optic chiasm ipRGCs sparsely innervate the dLGN (Hattar et al., 2006; Li and (where eye-specific axons cross) and appear to be a component of Schmidt, 2018) their interactions likely reflect intra-retinal signaling binocular vision development. as opposed to target maturation (ipRGC-to-dLGN axis). During development, spontaneous bursts of synchronized Interestingly, M1 ipRGCs project axon collaterals into the inner spatiotemporal neuron activity sweep across the retina (termed retina (Joo et al., 2013; Chew et al., 2017) and participate in both retinal waves) (Fig. 3A). These correlated bursts of activity are dendritic (Tufford et al., 2018) and axon collateral signaling to generated through distinct mechanisms over developmental time, amacrine cells (Zhang et al., 2008, 2012; Atkinson et al., 2013; and are thought to refine RGC synaptic connections with image- Newkirk et al., 2013; Prigge et al., 2016) – thus, these two signaling DEVELOPMENT

5 REVIEW Development (2020) 147, dev196535. doi:10.1242/dev.196535

A Interneuron-to-RGC signaling B Timeline and mechanism of retinal wave generation

GCL SAC BC ? Starburst amacrine cell

Phase I Bipolar cell Gap-junction

Phase II Cholinergic

Direction of wave activity wave of Direction Phase III Glutamatergic RGC Age P0 P10

CDRGC axons: Contralateral Ipsilateral Overlap

Central targets dLGN dLGN vLGN vLGN

Inter-RGC interactions Optic chiasm RGC gap-junctions ipRGCs R-R projections

Fig. 3. Inter-RGC interactions shape early retinal activity. (A) Retinal waves are mediated through release of acetylcholine from starburst amacrine cells (SACs), glutamate via bipolar cells (BC), or through gap-junction coupling between retinal ganglion cells (RGCs). The activity of these cells drives waves of depolarization across the ganglion cell layer (GCL, right) to central targets involved in binocular vision (C,D) and refines synapses between RGCs and their targets. (B) Over developmental time, retinal waves are generated via distinct mechanisms (cell within circle) with partial overlap. Phase I (∼E16-P0), gap- junction-mediated waves; phase II (∼P0-P10), cholinergic waves; and phase III (∼P10-P14), glutamatergic waves. (C) RGCs from each retina extend axons towards the brain and cross at the optic chiasm or continue along the same side (pink versus purple axons). (D) At the visual thalamus (dLGN, dorsal lateral geniculate nucleus; vLGN, ventral lateral geniculate nucleus), retinal waves drive refinement of retinal projections from the eye on the same side (ipsilateral; pink) or opposite side (contralateral; purple). Inter-RGC interactions (bottom) are considered to drive a portion of this refinement process, promoting segregation of projection and thus less overlap (black regions in dorsal LGN). ipRGCs, intrinsically photosensitive RGCs; R-R projections, retino-retinal projections. modalities may explain how ipRGCs shape retinal wave dynamics. projections, because the Unc5 axon guidance molecule they express Given that the photopigment melanopsin is unnecessary for retinal is both necessary and sufficient to generate R-R projections. wave initiation or wave properties, it is still unclear whether activity- Although it is difficult to manipulate or record activity of these dependent or independent mechanisms are employed by M1 processes, mathematical modeling suggests that R-R projections may ipRGCs to regulate intra-RGC and visual circuit development. provide inter-retinal synchrony to maximize bilateral eye-specific segregation (Murcia-Belmonte et al., 2019). This is especially true in RGC crosstalk at the optic chiasm shapes binocular vision organisms that have disparate size relationships between the retina Although ipRGCs appear to regulate signaling within the local and central targets (Murcia-Belmonte et al., 2019). Organisms with environment of the retina, some RGCs project their axons to the optic similarly sized retina and targets (zebrafish) appear to lack these chiasm and into the retina of the other eye (Fig. 3C). These structures, transient RGC projections and retinal Unc5 expression, primarily termed retino-retinal or ‘R-R projections’, have been described in relying on molecule-guided retinal mapping and less on retinal amphibians (Bohn and Stelzner, 1981; Humphrey and Beazley, 1985; waves. Conversely, in mice, in vivo recording of retinal waves at the Tóth and Straznicky, 1989; Tennant et al., 1993), birds (McLoon and superior colliculus reveals an unexpected level of correlation between Lund, 1982; Thanos, 1999) and mammals (Bunt and Lund, 1981; waves emerging from both retinae (Ackman et al., 2012), leading Braekevelt et al., 1986; Müller and Holländer, 1988; Nadal-Nicolás authors to speculate that R-R projections functionally synchronize et al., 2015; Tang et al., 2016). Initially, they were considered non- activity in each eye. functional or an experimental artifact, but recent work suggests that R-R projections reflect a small fraction of RGC projections, as the R-R projections likely serve a role during development of the visual majority direct their axons to central targets. Along their journey system. R-R projections have been traced to the GCL of the opposing from the retina to the brain, axons from both eyes converge at the retina, in which they closely associate with immature SACs optic chiasm (Fig. 3C), at which a portion cross over (contralateral (pacemakers of phase II retinal waves) (Fig. 3B; Murcia-Belmonte or c-RGC) and the remainder maintain their trajectory (ipsilateral or et al., 2019). These structures likely represent bona fide retinal i-RGC). These contra- and ipsilateral-projecting pathways are the DEVELOPMENT

6 REVIEW Development (2020) 147, dev196535. doi:10.1242/dev.196535 basis of binocular vision (Rasband et al., 2003) in vertebrates. The factor 15 (Fgf15), which serves as a chemoattractant for newly optic chiasm, where RGC axons cross, is a location where axon generated, migrating inhibitory interneurons (Su et al., 2020). guidance molecules are interpreted to be repulsive or attractive A large portion of input to the visual thalamus consists of axons (reviewed by Erskine and Herrera, 2007; Rasband et al., 2003). This originating from the cortex (corticothalamic axons), thalamic is largely accomplished by interactions between the niche and the reticular nucleus and various brainstem nuclei (Guido, 2018). intrinsic type of RGC (c-RGC or i-RGC) responding to these cues. These non-retinal inputs modulate thalamic signaling behavior and As previously discussed, Shh is expressed by RGCs and acts as a are integral to transmission of retinal input to multiple dLGN targets. potent mitogen both locally (RPC proliferation) and at the optic disc Given that both retinal and non-retinal axons terminate in the LGN, it (astrocyte precursor proliferation). This suggests that it is trafficked is not surprising that both timing and targeting are regulated via down the axon and released at distal locations (Wallace and Raff, axonal interactions. Retinal axons, which arrive at the dLGN early, 1999; Dakubo et al., 2003). Later in development, Shh is expressed limit dLGN innervation by corticothalamic axons (Brooks et al., by the earlier-born c-RGC population (Sánchez-Camacho and 2013; Seabrook et al., 2013) by inhibiting the degradation of the Bovolenta, 2008), whereas the corresponding Shh receptor Boc is repulsive chondroitin sulfate proteoglycan (CSPG) aggrecan (Brooks expressed by later-born i-RGCs (Fabre et al., 2010). Given the et al., 2013). This axon innervation pathway involves RGC regulation temporal sequence of birth and axon targeting, it is speculated that of dLGN interneurons that release aggrecanases (enzymes that break c-RGCs influence the targeting of i-RGCs. Consistent with these down aggrecan) and serves as a developmental switch to regulate observations, c-RGCs produce, traffic and deposit Shh in the optic timely innervation of the thalamus. Conversely, projections from the chiasm before the generation of i-RGCs (Peng et al., 2018). As retinal brainstem (ascending cholinergic input) rely on RGCs to promote development progresses, i-RGCs project their axon to the chiasm, are their timely arrival and axon arborization in the dLGN (Sokhadze repelled by Shh signaling and fail to cross the midline, and thus et al., 2018). As such, RGCs regulate local events (such as astrocyte maintain their ipsilateral trajectories (Peng et al., 2018; Ferent et al., signaling and interneuron recruitment) and long-range events (i.e. 2019). i-RGC competency to respond to Shh is mediated by timely recruitment of corticothalamic and brainstem projections) expression of the receptor Boc, which is both necessary and sufficient during thalamic development. for axon repulsion at the chiasm (Fabre et al., 2010). Taken together, Beyond the visual thalamus, RGCs project axons to other nuclei RGCs use multiple mechanisms to shape the development of the involved in image forming vision, such as the superior colliculus of binocular visual system – modulation of retinal waves, inter-retinal the midbrain (SC), as well as nuclei involved in image stabilization, signaling and regulation of axon guidance allow RGCs to shape including the medial terminal nucleus (MTN), dorsal terminal communication with central targets before the initiation of vision. nucleus (DTN) and nucleus of the optic tract (NOT). As in the dLGN, complementary ligand-receptor interactions recruit RGC- The roles of RGCs in central target development and subclass-specific axons to the MTN and SC (Osterhout et al., 2015; behavior Sun et al., 2015; Ito and Feldheim, 2018). However, whether RGCs The central portion of the visual system comprises brain regions influence the development of circuits, non-retinal input or cells dedicated to receiving, decoding and dispatching information within these targets remains to be explored. Given that a single RGC arriving from the retina. In mice, RGCs project their axons to more innervates multiple targets (Ellis et al., 2016), and known RGC than 40 unique regions of the brain (Morin and Studholme, 2014; types that contact the dLGN simultaneously innervate the SC, NOT, Martersteck et al., 2017), which we collectively refer to as ‘central DTN and MTN (Kay et al., 2011), it is likely that these central targets’. Retinal axons terminate in the hypothalamus, thalamus and targets all receive similar developmental input from RGCs. midbrain, and thus regulate a variety of behaviors that can be broadly categorized as image forming and non-image forming. In this section, ipRGCs regulate maturation of the circadian clock and circadian we describe our current understanding of how RGCs shape features of entrainment central target cells, influence the innervation of non-retinal inputs and The unique ability of ipRGCs to detect photons is matched by their guide the development of behaviors (Fig. 4). unique projections to central targets. In addition to the visual thalamus, ipRGC axons terminate in multiple nuclei, most notably RGCs in the development of image-forming central targets the suprachiasmatic nuclei (SCN), the intergeniculate leaflet (IGL) As presented in previous sections, RGCs are capable of regulating the and the olivary pretectal nucleus (OPN) (Hattar et al., 2006). These development of multiple cell types within a tissue, through diverse nuclei are collectively termed ‘non-image forming’ because they do mechanisms (activity, secreted factors and structure). This degree of not participate in conscious vision; rather, they are involved in regulation is true for thalamic targets such as the dLGN, in which behavioral and circadian processes (Fu et al., 2005). As ipRGCs are RGCs synapse onto thalamocortical (TC) relay neurons and inhibitory thought to exclusively express melanopsin, these cells are readily interneurons. Spontaneous retinal activity, in the form of retinal waves, accessed genetically and, therefore, much is known about their is largely responsible for the maturation of dLGN circuitry (Failor developmental influence on non-image forming central targets and et al., 2015), and developmental remodeling of TC relay neurons their behavioral output. (El-Danaf et al., 2015) and interneurons (Charalambakis et al., 2019). Throughout the day, rods, cones and melanopsin detect ambient In addition, layer-specific recruitment of dLGN inhibitory interneurons light, which is conveyed via ipRGC axons to the SCN (the circadian is accomplished by spontaneous activity via RGCs (Golding et al., pacemaker). Innervation of the SCN via ipRGCs takes place during 2014). RGC axons also provide a physical scaffold and secreted cues postnatal life in the mouse (McNeill et al., 2011; Chew et al., 2017), to guide development of the dLGN (activity-independent input). and ipRGCs serve as the primary retinal input to this structure Although multiple mechanisms may explain how RGCs recruit (Hatori et al., 2008; Ecker et al., 2010; Kofuji et al., 2016). This interneurons to the appropriate central target, recent transcriptional ipRGC-SCN signaling axis allows the organism to synchronize profiling of the LGN in the absence of retinal input provides some behavior with the light-dark cycle (called photoentrainment). In the insight into these complex interactions. Within the developing LGN, absence of an external stimulus or cue, the circadian clock has an

RGC axons stimulate local astrocytes to produce fibroblast growth endogenous free-running period which is close to – but not exactly – DEVELOPMENT

7 REVIEW Development (2020) 147, dev196535. doi:10.1242/dev.196535

Fig. 4. RGC-regulated central target development. (A) Projections from the A Central targets of RGCs – 40+ regions (mouse) Targets retina terminate in unique central target locations – more than 40 in the mouse brain SCN (Martersteck et al., 2017) – that correspond dLGN to regions of the hypothalamus (blue), vLGN thalamus (red) and midbrain (yellow). IGL Coronal brain sections highlight major targets of retinal ganglion cells (RGCs) in SC the hypothalamus (SCN, suprachiasmatic OPN nucleus), thalamus (dLGN, dorsal lateral geniculate nucleus; IGL, intergeniculate leaflet; vLGN, ventral lateral geniculate nucleus) and midbrain (OPN, olivary B Retina CentraCentrall tartargetsgets dduringuring ddevelopmentevelopment pretectal nucleus; SC, superior colliculus). (B) RGC projections from the retina influence the recruitment of interneurons RGCRGCss NNeuroneuron CirCircuitcuit NonNon-retinal-retinal via astrocytes, maturation of thalamic recrecruitmentruitment matmaturationuration iinnervationnnervation circuitry and non-retinal innervation of AActivityctivity central targets.

RelReleasedeased facfactorstors

Behavioral output

Key

Hypothalamus Thalamus Midbrain

Immature Maturing Non-RGC RGC Astrocyte interneuron interneuron projection axon

24 h (Herzog et al., 2017; Hastings et al., 2018). ipRGC activity is of neuropeptide Y (NPY) in IGL neurons projecting to the SCN necessary for acute entrainment of the circadian clock with the light- (Fernandez et al., 2020). Without ipRGC innervation and NPY dark cycle, but has been shown to also regulate the free-running release at the SCN, the ability to anticipate time-restricted feeding period of the circadian pacemaker in mice. Removal of the eyes cues is greatly diminished (Fernandez et al., 2020). Together with (enucleation) of mice at birth lengthens the circadian period, retinal input-driven thalamic development, these data lead us to whereas enucleation into adulthood (P60) has no effect on setting reason that RGC input is required to sculpt and shape the intrinsic the period, suggesting a crucial window for RGC input to shape properties, non-retinal inputs and behavioral output that emerge from SCN output and circadian behavior (Chew et al., 2017). Mice raised central targets in the brain, independently of their adult roles. in the absence of light or lacking M1 ipRGCs (Opn4DTA mutants) also have lengthened circadian periods, further implicating light- Leveraging transcriptomic and genetic tools to unravel RGC and activity-dependent ipRGC signaling as a potential mechanism type-specific regulation of visual system development for period setting. Thus, retinal input from ipRGCs is required This Review highlights the developmental roles of RGCs, roles that developmentally, to shape the period length of the clock, and shape and tune the visual system. As discussed, developmental RGC acutely, to synchronize the clock with the light-dark cycle. interactions are diverse and not limited to their adult synaptic partners. M1 ipRGC interactions with the SCN not only set the pace of the As we uncover the diversity of RGCs as a class, a few questions circadian clock, but also impact development of non-retinal SCN become apparent: what are the contributions of other RGC subclasses circuitry. The IGL provides input to the SCN and is involved in and types, if any, to visual system development? Is there a nonphotic entrainment of the circadian clock. In the absence of a mechanistic bias for certain RGC types within their regulatory roles light-dark cycle, an animal can behaviorally entrain to events that during development (synaptic, structural or peptide release)? occur at a predictable time across the circadian day, such as time- In the last decade, genetic approaches using Cre recombinase restricted feeding (Janik and Mrosovsky, 1994; Edelstein and Amir, mouse lines that target entire RGC subclasses have provided insight

1999). ipRGC innervation of the SCN is necessary for the expression into these questions. This is particularly true for the ipRGC subclass DEVELOPMENT

8 REVIEW Development (2020) 147, dev196535. doi:10.1242/dev.196535 that express Opn4 and can be accessed through the Opn4cre mouse combinations of at least two genes (Tran et al., 2019), dual- line (Ecker et al., 2010). The remarkably diverse influence of ipRGCs recombinase systems are currently implemented to study retinal on visual system development (Rao et al., 2013; Johnson et al., 2010; neuron types in the adult (Jo et al., 2018) and have the potential to be Tufford et al., 2018), circadian behavior (Güler et al., 2008; Chew applied to visual system development. Combining recombinase lines et al., 2017; Fernandez et al., 2020; Hatori et al., 2008), body (single or dual) with recombinase-dependent ablation/toxin alleles temperature (Rupp et al., 2019), mood (Fernandez et al., 2018; Huang (Mu et al., 2005) or signaling modifying alleles (Huang and Zeng, et al., 2019), learning (Fernandez et al., 2018) and sleep (Rupp et al., 2013; Madisen et al., 2015) would allow us to explore the importance 2019) have been assessed using the specificity of Opn4 expression in of each RGC type and potential activity-dependent or -independent combination with Cre-dependent ablation (Rosa26iDTR) and neuronal mechanisms on development of the visual system. In addition, silencing alleles (Rosa26TeNT). It is also clear that, within the ipRGC temporal control of ablation (Rosa26iDTR), silencing (hM4Di)or subclass, distinct RGC types are integral for the development of activation (hM3Dq) can be used to assess when RGC type-specific particular behaviors. These discoveries were made possible through signaling influences the developmental landscape of the visual intersectional genetics, with knowledge of RGC type-specific genes system. Considering that the influence of RGCs is not limited to a (e.g. non SCN-projecting M1 ipRGCs express Opn4 but not Brn3b) single cell type within the visual system, it will be important to and intersectional alleles that allow for recombinase-mediated determine the broader influence of these signaling hubs – particularly manipulation of the cell (Opn4cre; Pou4f2z-DTA). It is unlikely that through unbiased techniques, such as scRNA-seq, proteomics and ipRGC types are alone in their roles as developmental regulators. behavioral analysis (Fig. 5). Together, scRNA-seq data and genetics Given that the entire RGC repertoire is established rather early, it is may shed light on the emerging developmental roles of RGCs. likely that many RGC types and subclasses contribute to development of the retinal and central landscapes. Conclusion Recent RGC single-cell RNA-sequencing (scRNA-seq) and To summarize, we have reviewed the emerging roles of RGCs in the physiological profiling studies provide us with a foundation to development of the visual system. Along the visual pathway, from address RGC type-specific developmental questions (Baden et al., retina to targets, we have discussed how RGC activity-dependent 2016; Rheaume et al., 2018; Tran et al., 2019). Sequencing has and activity-independent inputs regulate the development of diverse revealed candidate marker genes that may exist as recombinase lines cell types within a given niche (neuronal and non-neuronal). Many (Cre or Flp), which can offer us genetic access to specific RGC types. questions remain to be addressed, such as whether all RGC types are Although these studies suggest that RGC types can be described by equally poised to regulate development, or which components of

Fig. 5. Deciphering the roles of RGC type Recombinase-dependent unique RGC types on the RGC diversity genetic access RGC manipulation development of the visual system. Molecular profiling To address the fundamental roles of Marker 1 Type #1 Ablation alleles each of the retinal ganglion cell (RGC) Marker 2 types requires a comprehensive Marker 3 Marker 1 Pou4f2 understanding of the typology of these Marker 4 Cre DTA Marker 5 cells (RGC diversity). The diversity of ... Rosa26 Marker 2 RGCs can be defined by their unique DTR Flp transcriptomes (Tran et al., 2019) or electrophysiological responses to visual stimuli (Baden et al., 2016), or a Type #2 Silencing alleles combination of the two. From this, we Marker 3 Rosa26 can define unique combinations of Cre TeNT genes that define types of RGCs (e.g. marker 1 and 2 define type #1, and Marker 4 Rosa26 marker 3 and 4 define type #2, etc.) Flp Physiological hM4Di and gain genetic access to these cells profiling by using a combination of recombinase types (e.g. Cre, Flp) driven by subclass-specific genes. Furthermore, genetic access to RGC types would allow us to test whether the cell or its activity is required. Intersectional recombinase- dependent toxin lines (DTA, diphtheria toxin A subunit; DTR, diphtheria toxin receptor) or silencing lines (hM4Di, human muscarinic receptor 4 coupled to Gi; TeNT, tetanus toxin) can be applied with RGC type-specific recombinase(s). Finally, as RGCs regulate intra- and extra-retinal Retinal development: Central development: Organism behavior: development, it will be vital to assess Single-cell transcriptomics Projection mapping Visual tasks the changes that occur within and outside the retina to elucidate the Cell number and diversity Physiology and circuit maturation Circadian behavior developmental roles of RGC types. DEVELOPMENT

9 REVIEW Development (2020) 147, dev196535. doi:10.1242/dev.196535 vision are a consequence of developmental or adult activity of Bohn, R. C. and Stelzner, D. J. (1981). The aberrant retino-retinal projection during RGCs. With the derivation of new tools and ‘-omics’ datasets for optic nerve regeneration in the frog. II. Anterograde labeling with horseradish peroxidase. J. Comp. Neurol. 196, 621-632. doi:10.1002/cne.901960408 RGCs, we can begin to determine the RGC-autonomous, non- Braekevelt, C. R., Beazley, L. D., Dunlop, S. A. and Darby, J. E. (1986). Numbers autonomous and type-specific roles in shaping and establishing the of axons in the optic nerve and of retinal ganglion cells during development in the visual system – from molecules and synapses, to circuitry and marsupial Setonix brachyurus. Dev. Brain Res. 25, 117-125. doi:10.1016/0165- 3806(86)90158-6 behavior. Clinically, these forms of integrative multi-system Brodie-Kommit, J., Clark, B. S., Shi, Q., Shiau, F., Kim, D. W., Langel, J., Sheely, analyses will undoubtedly influence our understanding of how C., Schmidt, T., Badea, T., Glaser, T. et al. (2020). Atoh7-independent early human RGC loss in conditions such as anophthalmia, primary specification of retinal ganglion cell identity. bioRxiv. doi:10.1101/2020.05.27. congenital glaucoma (Wilson and Di Polo, 2012) and Atoh7 loss-of- 116954 Brooks, J. M., Su, J., Levy, C., Wang, J. S., Seabrook, T. A., Guido, W. and Fox, function (Prasov et al., 2012; Atac et al., 2019) influence visual M. A. (2013). A molecular mechanism regulating the timing of corticogeniculate system development and behavior beyond conscious vision. innervation. Cell Rep. 5, 573-581. doi:10.1016/j.celrep.2013.09.041 Brown, N. L., Patel, S., Brzezinski, J. and Glaser, T. (2001). Math5 is required for Acknowledgements retinal ganglion cell and optic nerve formation. Development 128, 2497-2508. We would like to thank our reviewers, Allie Pendery, Brian A. Upton and Dr Joshua Bunt, S. M. and Lund, R. D. (1981). Development of a transient retino-retinal R. Sanes for their helpful insight while preparing this Review. pathway in hooded and albino rats. Brain Res. 211, 399-404. doi:10.1016/0006- 8993(81)90712-5 Burbridge, T. J., Xu, H.-P., Ackman, J. B., Ge, X., Zhang, Y., Ye, M.-J., Zhou, Z. J., Competing interests Xu, J., Contractor, A. and Crair, M. C. (2014). Visual circuit development The authors declare no competing or financial interests. requires patterned activity mediated by retinal acetylcholine receptors. Neuron 84, 1049-1064. doi:10.1016/j.neuron.2014.10.051 Funding Burne, J. F. and Raff, M. C. (1997). Retinal ganglion cell axons drive the This work was supported by the National Institutes of Health (R01 EY027077 and proliferation of astrocytes in the developing rodent optic nerve. Neuron 18, R01 EY027711 to R.A.L.), in addition to funds provided by the Goldman Chair of the 223-230. doi:10.1016/S0896-6273(00)80263-9 Abrahamson Pediatric Eye Institute at Cincinnati Children’s Hospital Medical Center. Caval-Holme, F., Zhang, Y. and Feller, M. B. (2019). Gap junction coupling shapes Deposited in PMC for release after 12 months. the encoding of light in the developing retina. Curr. Biol. 29, 4024-4035.e5. doi:10. 1016/j.cub.2019.10.025 References Cayouette, M., Barres, B. A. and Raff, M. (2003). Importance of intrinsic Ackman, J. B., Burbridge, T. J. and Crair, M. C. (2012). Retinal waves coordinate mechanisms in cell fate decisions in the developing rat retina. Neuron 40, patterned activity throughout the developing visual system. Nature 490, 219-225. 897-904. doi:10.1016/S0896-6273(03)00756-6 Cepko, C. (2014). Intrinsically different retinal progenitor cells produce specific types doi:10.1038/nature11529 Akopian, A., Atlasz, T., Pan, F., Wong, S., Zhang, Y., Völgyi, B., Paul, D. L. and of progeny. Nature Rev. Neurosci. 15, 615-627. doi:10.1038/nrn3767 Charalambakis, N. E., Govindaiah, G., Campbell, P. W. and Guido, W. (2019). Bloomfield, S. A. (2014). Gap junction-mediated death of retinal neurons is Developmental remodeling of thalamic interneurons requires retinal signaling. connexin and insult specific: a potential target for neuroprotection. J. Neurosci. 34, J. Neurosci. 39, 3856-3866. doi:10.1523/JNEUROSCI.2224-18.2019 10582-10591. doi:10.1523/JNEUROSCI.1912-14.2014 Chew, K. S., Renna, J. M., McNeill, D. S., Fernandez, D. C., Keenan, W. T., Altshuler, D. and Cepko, C. (1992). A temporally regulated, diffusible activity is Thomsen, M. B., Ecker, J. L., Loevinsohn, G. S., VanDunk, C., Vicarel, D. C. required for rod photoreceptor development in vitro. Development 114, 947-957. et al. (2017). A subset of ipRGCs regulates both maturation of the circadian clock Atac, D. G., Koller, S., Hanson, J. V. M., Feil, S., Tiwari, A., Bahr, A., Baehr, L., and segregation of retinogeniculate projections in mice. eLife 6, e22861. doi:10. Magyar, I., Kottke, R., Gerth-Kahlert, C. et al. (2019). Atonal homolog 7 7554/eLife.22861 (ATOH7) loss-of-function mutations in predominant bilateral optic nerve Cristante, E., Liyanage, S. E., Sampson, R. D., Kalargyrou, A., De Rossi, G., hypoplasia. Hum. Mol. Genet. 29, 132-148. doi:10.1093/hmg/ddz268 Rizzi, M., Hoke, J., Ribeiro, J., Maswood, R. N., Duran, Y. et al. (2018). Late Atkinson, C. L., Feng, J. and Zhang, D.-Q. (2013). Functional integrity and neuroprogenitors contribute to normal retinal vascular development in a Hif2a- modification of retinal dopaminergic neurons in the rd1 mutant mouse: roles of dependent manner. Development 145, dev157511. doi:10.1242/dev.157511 melanopsin and GABA. J. Neurophysiol. 109, 1589-1599. doi:10.1152/jn.00786. Dakubo, G. D., Wang, Y. P., Mazerolle, C., Campsall, K., McMahon, A. P. and 2012 Wallace, V. A. (2003). Retinal ganglion cell-derived sonic hedgehog signaling is Baden, T., Berens, P., Franke, K., Román Rosón, M., Bethge, M. and Euler, T. required for optic disc and stalk neuroepithelial cell development. Development (2016). The functional diversity of retinal ganglion cells in the mouse. Nature 529, 130, 2967-2980. doi:10.1242/dev.00515 345-350. doi:10.1038/nature16468 Demarque, M., Represa, A., Becq, H., Khalilov, I., Ben-Ari, Y. and Aniksztejn, L. Baden, T., Euler, T. and Berens, P. (2020). Understanding the retinal basis of vision (2002). Paracrine intercellular communication by a Ca2+- and SNARE- across species. Nature Rev. Neurosci. 21, 5-20. doi:10.1038/s41583-019-0242-1 independent release of GABA and glutamate prior to synapse formation. Bai, L., Kiyama, T., Li, H. and Wang, S. W. (2014). Birth of cone bipolar cells, but not Neuron 36, 1051-1061. doi:10.1016/S0896-6273(02)01053-X rod bipolar cells, is associated with existing RGCs. PLoS ONE 9, e83686. doi:10. Dhande, O. S., Stafford, B. K., Lim, J.-H. A. and Huberman, A. D. (2015). 1371/journal.pone.0083686 Contributions of retinal ganglion cells to subcortical visual processing and Bansal, A., Singer, J. H., Hwang, B. J., Xu, W., Beaudet, A. and Feller, M. B. behaviors. Annu. Rev. Vis. Sci. 1, 291-328. doi:10.1146/annurev-vision-082114- (2000). Mice lacking specific nicotinic acetylcholine receptor subunits exhibit 035502 dramatically altered spontaneous activity patterns and reveal a limited role for Duan, X., Krishnaswamy, A., Laboulaye, M. A., Liu, J., Peng, Y.-R., Yamagata, retinal waves in forming ON and OFF circuits in the inner retina. J. Neurosci. 20, M., Toma, K. and Sanes, J. R. (2018). Cadherin combinations recruit dendrites of 7672-7681. doi:10.1523/JNEUROSCI.20-20-07672.2000 distinct retinal neurons to a shared interneuronal scaffold. Neuron 99, Belluardo, N., Mudo,̀ G., Trovato-Salinaro, A., Le Gurun, S., Charollais, A., 1145-1154.e6. doi:10.1016/j.neuron.2018.08.019 Ecker, J. L., Dumitrescu, O. N., Wong, K. Y., Alam, N. M., Chen, S.-K., LeGates, Serre-Beinier, V., Amato, G., Haefliger, J.-A., Meda, P. and Condorelli, D. F. T., Renna, J. M., Prusky, G. T., Berson, D. M. and Hattar, S. (2010). Melanopsin- (2000). Expression of connexin36 in the adult and developing rat brain. Brain Res. expressing retinal ganglion-cell photoreceptors: cellular diversity and role in 865, 121-138. doi:10.1016/S0006-8993(00)02300-3 pattern vision. Neuron 67, 49-60. doi:10.1016/j.neuron.2010.05.023 Berson, D. M., Dunn, F. A. and Takao, M. (2002). Phototransduction by retinal Edelstein, K. and Amir, S. (1999). The role of the intergeniculate leaflet in ganglion cells that set the circadian clock. Science 295, 1070-1073. doi:10.1126/ entrainment of circadian rhythms to a skeleton photoperiod. J. Neurosci. 19, science.1067262 372-380. doi:10.1523/JNEUROSCI.19-01-00372.1999 Biswas, S., Cottarelli, A. and Agalliu, D. (2020). Neuronal and glial regulation of Edwards, M. M., McLeod, D. S., Li, R., Grebe, R., Bhutto, I., Mu, X. and Lutty, CNS angiogenesis and barriergenesis. Development 147, dev182279. doi:10. G. A. (2012). The deletion of Math5 disrupts retinal blood vessel and glial 1242/dev.182279 development in mice. Exp. Eye Res. 96, 147-156. doi:10.1016/j.exer.2011.12.005 Blankenship, A. G. and Feller, M. B. (2010). Mechanisms underlying spontaneous El-Danaf, R. N., Krahe, T. E., Dilger, E. K., Bickford, M. E., Fox, M. A. and Guido, patterned activity in developing neural circuits. Nature Rev. Neurosci. 11, 18-29. W. (2015). Developmental remodeling of relay cells in the dorsal lateral geniculate doi:10.1038/nrn2759 nucleus in the absence of retinal input. Neural Dev. 10, 19. doi:10.1186/s13064- Blankenship, A. G., Hamby, A. M., Firl, A., Vyas, S., Maxeiner, S., Willecke, K. 015-0046-6 and Feller, M. B. (2011). The role of neuronal connexins 36 and 45 in shaping Ellis, E. M., Gauvain, G., Sivyer, B. and Murphy, G. J. (2016). Shared and distinct spontaneous firing patterns in the developing retina. J. Neurosci. 31, 9998-10008. retinal input to the mouse superior colliculus and dorsal lateral geniculate nucleus.

doi:10.1523/JNEUROSCI.5640-10.2011 J. Neurophysiol. 116, 602-610. doi:10.1152/jn.00227.2016 DEVELOPMENT

10 REVIEW Development (2020) 147, dev196535. doi:10.1242/dev.196535

Erskine, L. and Herrera, E. (2007). The retinal ganglion cell axon’s journey: insights Hattar, S., Liao, H.-W., Takao, M., Berson, D. M. and Yau, K.-W. (2002). into molecular mechanisms of axon guidance. Dev. Biol. 308, 1-14. doi:10.1016/j. Melanopsin-containing retinal ganglion cells: architecture, projections, and ydbio.2007.05.013 intrinsic photosensitivity. Science 295, 1065-1070. doi:10.1126/science.1069609 Fabre, P. J., Shimogori, T. and Charron, F. (2010). Segregation of ipsilateral retinal Hattar, S., Kumar, M., Park, A., Tong, P., Tung, J., Yau, K.-W. and Berson, D. M. ganglion cell axons at the optic chiasm requires the Shh receptor Boc. J. Neurosci. (2006). Central projections of melanopsin-expressing retinal ganglion cells in the 30, 266-275. doi:10.1523/JNEUROSCI.3778-09.2010 mouse. J. Comp. Neurol. 497, 326-349. doi:10.1002/cne.20970 Failor, S., Chapman, B. and Cheng, H.-J. (2015). Retinal waves regulate afferent He, J., Zhang, G., Almeida, A. D., Cayouette, M., Simons, B. D. and Harris, W. A. terminal targeting in the early visual pathway. Proc. Natl. Acad. Sci. USA 112, (2012). How variable clones build an invariant retina. Neuron 75, 786-798. doi:10. E2957-E2966. doi:10.1073/pnas.1506458112 1016/j.neuron.2012.06.033 Ferent, J., Giguere,̀ F., Jolicoeur, C., Morin, S., Michaud, J.-F., Makihara, S., Herzog, E. D., Hermanstyne, T., Smyllie, N. J. and Hastings, M. H. (2017). Yam, P. T., Cayouette, M. and Charron, F. (2019). Boc Acts via Numb as a Shh- Regulating the suprachiasmatic nucleus (scn) circadian clockwork: interplay dependent endocytic platform for Ptch1 internalization and Shh-mediated axon between cell-autonomous and circuit-level mechanisms. Cold Spring Harb. guidance. Neuron 102, 1157-1171.e5. doi:10.1016/j.neuron.2019.04.003 Perspect. Biol. 9, a027706. doi:10.1101/cshperspect.a027706 Fernandez, D. C., Fogerson, P. M., Lazzerini Ospri, L., Thomsen, M. B., Layne, Huang, Z. J. and Zeng, H. (2013). Genetic approaches to neural circuits in the R. M., Severin, D., Zhan, J., Singer, J. H., Kirkwood, A., Zhao, H. et al. (2018). mouse. Annu. Rev. Neurosci. 36, 183-215. doi:10.1146/annurev-neuro-062012- Light affects mood and learning through distinct retina-brain pathways. Cell 175, 170307 71-84.e18. doi:10.1016/j.cell.2018.08.004 Huang, L., Xi, Y., Peng, Y., Yang, Y., Huang, X., Fu, Y., Tao, Q., Xiao, J., Yuan, T., Fernandez, D. C., Komal, R., Langel, J., Ma, J., Duy, P. Q., Penzo, M. A., Zhao, H. An, K. et al. (2019). A visual circuit related to habenula underlies the and Hattar, S. (2020). Retinal innervation tunes circuits that drive nonphotic antidepressive effects of light therapy. Neuron 102, 128-142.e8. doi:10.1016/j. entrainment to food. Nature 581, 194-198. doi:10.1038/s41586-020-2204-1 neuron.2019.01.037 Firth, S. I., Wang, C.-T. and Feller, M. B. (2005). Retinal waves: mechanisms and Huberman, A. D., Feller, M. B. and Chapman, B. (2008). Mechanisms underlying function in visual system development. Cell Calcium 37, 425-432. doi:10.1016/j. development of visual maps and receptive fields. Annu. Rev. Neurosci. 31, ceca.2005.01.010 479-509. doi:10.1146/annurev.neuro.31.060407.125533 Fruttiger, M. (2007). Development of the retinal vasculature. Angiogenesis 10, Humphrey, M. F. and Beazley, L. D. (1985). Retinal ganglion cell death during optic 77-88. doi:10.1007/s10456-007-9065-1 nerve regeneration in the frog Hyla moorei. J. Comp. Neurol. 236, 382-402. doi:10. Fruttiger, M., Calver, A. R., Krüger, W. H., Mudhar, H. S., Michalovich, D., 1002/cne.902360307 Takakura, N., Nishikawa, S. I. and Richardson, W. D. (1996). PDGF mediates a Ito, S. and Feldheim, D. A. (2018). The mouse superior colliculus: an emerging neuron-astrocyte interaction in the developing retina. Neuron 17, 1117-1131. model for studying circuit formation and function. Front. Neural Circuits 12, 10. doi:10.1016/S0896-6273(00)80244-5 doi:10.3389/fncir.2018.00010 Fu, Y., Liao, H.-W., Do, M. T. H. and Yau, K.-W. (2005). Non-image-forming ocular Jadhav, A. P., Cho, S.-H. and Cepko, C. L. (2006). Notch activity permits retinal photoreception in vertebrates. Curr. Opin. Neurobiol. 15, 415-422. doi:10.1016/j. cells to progress through multiple progenitor states and acquire a stem cell conb.2005.06.011 property. Proc. Natl Acad. Sci. USA 103, 18998-19003. doi:10.1073/pnas. Gan, L., Xiang, M., Zhou, L., Wagner, D. S., Klein, W. H. and Nathans, J. (1996). 0608155103 Janik, D. and Mrosovsky, N. (1994). Intergeniculate leaflet lesions and POU domain factor Brn-3b is required for the development of a large set of retinal behaviorally-induced shifts of circadian rhythms. Brain Res. 651, 174-182. ganglion cells. Proc. Natl. Acad. Sci. USA 93, 3920-3925. doi:10.1073/pnas.93.9. doi:10.1016/0006-8993(94)90695-5 3920 Jensen, A. M. and Wallace, V. A. (1997). Expression of Sonic hedgehog and its Ghiasvand, N. M., Rudolph, D. D., Mashayekhi, M., Brzezinski, J. A., IV, putative role as a precursor cell mitogen in the developing mouse retina. Goldman, D. and Glaser, T. (2011). Deletion of a remote enhancer near ATOH7 Development 124, 363-371. disrupts retinal neurogenesis, causing NCRNA disease. Nature Neurosci. 14, Jo, A., Xu, J., Deniz, S., Cherian, S., DeVries, S. H. and Zhu, Y. (2018). 578-586. doi:10.1038/nn.2798 Intersectional strategies for targeting amacrine and ganglion cell types in the Gnanaguru, G., Bachay, G., Biswas, S., Pinzón-Duarte, G., Hunter, D. D. and mouse retina. Front. Neural Circuits 12, 66. doi:10.3389/fncir.2018.00066 Brunken, W. J. (2013). Laminins containing the β2 and γ3 chains regulate Johnson, J., Wu, V., Donovan, M., Majumdar, S., Renterıa,́ R. C., Porco, T., Van astrocyte migration and angiogenesis in the retina. Development 140, 2050-2060. Gelder, R. N. and Copenhagen, D. R. (2010). Melanopsin-dependent light doi:10.1242/dev.087817 avoidance in neonatal mice. Proc. Natl Acad. Sci. USA 107, 17374-17378. doi:10. Goldberg, J. L., Espinosa, J. S., Xu, Y., Davidson, N., Kovacs, G. T. A. and 1073/pnas.1008533107 Barres, B. A. (2002). Retinal ganglion cells do not extend axons by default. Joo, H. R., Peterson, B. B., Dacey, D. M., Hattar, S. and Chen, S. K. (2013). Neuron 33, 689-702. doi:10.1016/S0896-6273(02)00602-5 Recurrent axon collaterals of intrinsically photosensitive retinal ganglion cells. Vis. Golding, B., Pouchelon, G., Bellone, C., Murthy, S., Di Nardo, A. A., Govindan, Neurosci. 30, 175-182. doi:10.1017/S0952523813000199 ̈ S., Ogawa, M., Shimogori, T., Luscher, C., Dayer, A. et al. (2014). Retinal input Kay, J. N., Finger-Baier, K. C., Roeser, T., Staub, W. and Baier, H. (2001). Retinal directs the recruitment of inhibitory interneurons into thalamic visual circuits. ganglion cell genesis requires lakritz, a Zebrafish atonal Homolog. Neuron 30, Neuron 81, 1057-1069. doi:10.1016/j.neuron.2014.01.032 725-736. doi:10.1016/S0896-6273(01)00312-9 Gomes, F. L. A. F., Zhang, G., Carbonell, F., Correa, J. A., Harris, W. A., Simons, Kay, J. N., Roeser, T., Mumm, J. S., Godinho, L., Mrejeru, A., Wong, R. O. L. and B. D. and Cayouette, M. (2011). Reconstruction of rat retinal progenitor cell Baier, H. (2004). Transient requirement for ganglion cells during assembly of lineages in vitro reveals a surprising degree of stochasticity in cell fate decisions. retinal synaptic layers. Development 131, 1331-1342. doi:10.1242/dev.01040 Development 138, 227-235. doi:10.1242/dev.059683 Kay, J. N., De la Huerta, I., Kim, I.-J., Zhang, Y., Yamagata, M., Chu, M. W., Guido, W. (2018). Development, form, and function of the mouse visual thalamus. Meister, M. and Sanes, J. R. (2011). Retinal ganglion cells with distinct J. Neurophysiol. 120, 211-225. doi:10.1152/jn.00651.2017 directional preferences differ in molecular identity, structure, and central ̈ Guler, A. D., Ecker, J. L., Lall, G. S., Haq, S., Altimus, C. M., Liao, H.-W., Barnard, projections. J. Neurosci. 31, 7753-7762. doi:10.1523/JNEUROSCI.0907-11.2011 A. R., Cahill, H., Badea, T. C., Zhao, H. et al. (2008). Melanopsin cells are the Kerschensteiner, D., Morgan, J. L., Parker, E. D., Lewis, R. M. and Wong, principal conduits for rod-cone input to non-image-forming vision. Nature 453, R. O. L. (2009). Neurotransmission selectively regulates synapse formation in 102-105. doi:10.1038/nature06829 parallel circuits in vivo. Nature 460, 1016-1020. doi:10.1038/nature08236 Han, Y. and Massey, S. C. (2005). Electrical synapses in retinal ON cone bipolar Kim, J., Wu, H.-H., Lander, A. D., Lyons, K. M., Matzuk, M. M. and Calof, A. L. cells: subtype-specific expression of connexins. Proc. Natl. Acad. Sci. USA 102, (2005). GDF11 controls the timing of progenitor cell competence in developing 13313-13318. doi:10.1073/pnas.0505067102 retina. Science 308, 1927-1930. doi:10.1126/science.1110175 Hansen, K. A., Torborg, C. L., Elstrott, J. and Feller, M. B. (2005). Expression and Kirkby, L. A. and Feller, M. B. (2013). Intrinsically photosensitive ganglion cells function of the neuronal gap junction protein connexin 36 in developing contribute to plasticity in retinal wave circuits. Proc. Natl Acad. Sci. USA 110, mammalian retina. J. Comp. Neurol. 493, 309-320. doi:10.1002/cne.20759 12090-12095. doi:10.1073/pnas.1222150110 Hashimoto, T., Zhang, X.-M., Chen, B. Y. and Yang, X.-J. (2006). VEGF activates Kofuji, P., Mure, L. S., Massman, L. J., Purrier, N., Panda, S. and Engeland, divergent intracellular signaling components to regulate retinal progenitor cell W. C. (2016). Intrinsically Photosensitive Retinal Ganglion Cells (ipRGCs) are proliferation and neuronal differentiation. Development 133, 2201-2210. doi:10. necessary for light entrainment of peripheral clocks. PLoS ONE 11, e0168651. 1242/dev.02385 doi:10.1371/journal.pone.0168651 Hastings, M. H., Maywood, E. S. and Brancaccio, M. (2018). Generation of Kondo, H., Matsushita, I., Tahira, T., Uchio, E. and Kusaka, S. (2016). Mutations circadian rhythms in the suprachiasmatic nucleus. Nature Rev. Neurosci. 19, in ATOH7 gene in patients with nonsyndromic congenital retinal nonattachment 453-469. doi:10.1038/s41583-018-0026-z and familial exudative vitreoretinopathy. Ophthalmic Genet. 37, 462-464. doi:10. Hatori, M., Le, H., Vollmers, C., Keding, S. R., Tanaka, N., Schmedt, C., Jegla, T. 3109/13816810.2015.1120316 and Panda, S. (2008). Inducible ablation of melanopsin-expressing retinal Lee, S.-C., Cruikshank, S. J. and Connors, B. W. (2010). Electrical and chemical ganglion cells reveals their central role in non-image forming visual responses. synapses between relay neurons in developing thalamus. J. Physiol. 588,

PLoS ONE 3, e2451. doi:10.1371/journal.pone.0002451 2403-2415. doi:10.1113/jphysiol.2010.187096 DEVELOPMENT

11 REVIEW Development (2020) 147, dev196535. doi:10.1242/dev.196535

Li, J. Y. and Schmidt, T. M. (2018). Divergent projection patterns of M1 ipRGC establish an angiogenic template during retinal development. Glia 65, 1697-1716. subtypes. J. Comp. Neurol. 526, 2010-2018. doi:10.1002/cne.24469 doi:10.1002/glia.23189 Liu, W., Mo, Z. and Xiang, M. (2001). The Ath5 proneural genes function upstream Peng, J., Fabre, P. J., Dolique, T., Swikert, S. M., Kermasson, L., Shimogori, T. of Brn3 POU domain transcription factor genes to promote retinal ganglion cell and Charron, F. (2018). Sonic hedgehog is a remotely produced cue that controls development. Proc. Natl. Acad. Sci USA 98, 1649-1654. doi:10.1073/pnas.98.4. axon guidance trans-axonally at a midline choice point. Neuron 97, 326-340.e4. 1649 doi:10.1016/j.neuron.2017.12.028 Madisen, L., Garner, A. R., Shimaoka, D., Chuong, A. S., Klapoetke, N. C., Li, L., Prasov, L., Masud, T., Khaliq, S., Mehdi, S. Q., Abid, A., Oliver, E. R., Silva, E. D., van der Bourg, A., Niino, Y., Egolf, L., Monetti, C. et al. (2015). Transgenic mice Lewanda, A., Brodsky, M. C., Borchert, M. et al. (2012). ATOH7 mutations for intersectional targeting of neural sensors and effectors with high specificity and cause autosomal recessive persistent hyperplasia of the primary vitreous. Hum. performance. Neuron 85, 942-958. doi:10.1016/j.neuron.2015.02.022 Mol. Genet. 21, 3681-3694. doi:10.1093/hmg/dds197 Martersteck, E. M., Hirokawa, K. E., Evarts, M., Bernard, A., Duan, X., Li, Y., Ng, Prigge, C. L., Yeh, P.-T., Liou, N.-F., Lee, C.-C., You, S.-F., Liu, L.-L., McNeill, L., Oh, S. W., Ouellette, B., Royall, J. J. et al. (2017). Diverse central projection D. S., Chew, K. S., Hattar, S., Chen, S.-K. et al. (2016). M1 ipRGCs influence patterns of retinal ganglion cells. Cell Rep. 18, 2058-2072. doi:10.1016/j.celrep. visual function through retrograde signaling in the retina. J. Neurosci. 36, 2017.01.075 7184-7197. doi:10.1523/JNEUROSCI.3500-15.2016 Masland, R. H. (2012). The neuronal organization of the retina. Neuron 76, 266-280. Provencio, I., Rollag, M. D. and Castrucci, A. M. (2002). Photoreceptive net in the doi:10.1016/j.neuron.2012.10.002 mammalian retina. This mesh of cells may explain how some blind mice can still Maxeiner, S., Krüger, O., Schilling, K., Traub, O., Urschel, S. and Willecke, K. tell day from night. Nature 415, 493. doi:10.1038/415493a (2003). Spatiotemporal transcription of connexin45 during brain development Rao, S., Chun, C., Fan, J., Kofron, J. M., Yang, M. B., Hegde, R. S., Ferrara, N., results in neuronal expression in adult mice. Neuroscience 119, 689-700. doi:10. Copenhagen, D. R. and Lang, R. A. (2013). A direct and melanopsin-dependent 1016/S0306-4522(03)00077-0 fetal light response regulates mouse eye development. Nature 494, 243-246. McLaughlin, T., Torborg, C. L., Feller, M. B. and O’Leary, D. D. M. (2003). doi:10.1038/nature11823 Retinotopic map refinement requires spontaneous retinal waves during a brief Rasband, K., Hardy, M. and Chien, C.-B. (2003). Generating X. Neuron 39, critical period of development. Neuron 40, 1147-1160. doi:10.1016/S0896- 885-888. doi:10.1016/S0896-6273(03)00563-4 6273(03)00790-6 Renna, J. M., Weng, S. and Berson, D. M. (2011). Light acts through melanopsin to McLoon, S. C. and Lund, R. D. (1982). Transient retinofugal pathways in the alter retinal waves and segregation of retinogeniculate afferents. Nat. Neurosci. developing chick. Exp. Brain Res. 45, 277-284. doi:10.1007/BF00235788 14, 827-829. doi:10.1038/nn.2845 McNeill, D. S., Sheely, C. J., Ecker, J. L., Badea, T. C., Morhardt, D., Guido, W. Renna, J. M., Chellappa, D. K., Ross, C. L., Stabio, M. E. and Berson, D. M. and Hattar, S. (2011). Development of melanopsin-based irradiance detecting (2015). Melanopsin ganglion cells extend dendrites into the outer retina during circuitry. Neural Dev. 6, 8. doi:10.1186/1749-8104-6-8 early postnatal development. Dev. Neurobiol. 75, 935-946. doi:10.1002/dneu. Mills, S. L., O’Brien, J. J., Li, W., O’Brien, J. and Massey, S. C. (2001). Rod 22260 pathways in the mammalian retina use connexin 36. J. Comp. Neurol. 436, Rheaume, B. A., Jereen, A., Bolisetty, M., Sajid, M. S., Yang, Y., Renna, K., Sun, 336-350. doi:10.1002/cne.1071 L., Robson, P. and Trakhtenberg, E. F. (2018). Single cell transcriptome profiling Missaire, M. and Hindges, R. (2015). The role of cell adhesion molecules in visual of retinal ganglion cells identifies cellular subtypes. Nat. Commun. 9, 2759. doi:10. circuit formation: from neurite outgrowth to maps and synaptic specificity. Dev. 1038/s41467-018-05134-3 Neurobiol. 75, 569-583. doi:10.1002/dneu.22267 Rupp, A. C., Ren, M., Altimus, C. M., Fernandez, D. C., Richardson, M., Turek, F., Morgan, J. L., Schubert, T. and Wong, R. O. L. (2008). Developmental patterning Hattar, S. and Schmidt, T. M. (2019). Distinct ipRGC subpopulations mediate of glutamatergic synapses onto retinal ganglion cells. Neural Dev. 3, 8. doi:10. light’s acute and circadian effects on body temperature and sleep. eLife 8, 1186/1749-8104-3-8 e44358. doi:10.7554/eLife.44358 Morin, L. P. and Studholme, K. M. (2014). Retinofugal projections in the mouse. Sánchez-Camacho, C. and Bovolenta, P. (2008). Autonomous and non- J.Comp.Neurol. 522, 3733-3753. doi:10.1002/cne.23635 autonomous Shh signalling mediate the in vivo growth and guidance of mouse Moshiri, A., Gonzalez, E., Tagawa, K., Maeda, H., Wang, M., Frishman, L. J. and retinal ganglion cell axons. Development 135, 3531-3541. doi:10.1242/dev. Wang, S. W. (2008). Near complete loss of retinal ganglion cells in the math5/ 023663 brn3b double knockout elicits severe reductions of other cell types during retinal Sanes, J. R. and Zipursky, S. L. (2010). Design principles of insect and vertebrate development. Dev. Biol. 316, 214-227. doi:10.1016/j.ydbio.2008.01.015 visual systems. Neuron 66, 15-36. doi:10.1016/j.neuron.2010.01.018 Mu, X., Fu, X., Sun, H., Liang, S., Maeda, H., Frishman, L. J. and Klein, W. H. Sanes, J. R. and Zipursky, S. L. (2020). Synaptic specificity, recognition (2005). Ganglion cells are required for normal progenitor- cell proliferation but not molecules, and assembly of neural circuits. Cell 181, 536-556. doi:10.1016/j. cell-fate determination or patterning in the developing mouse retina. Curr. Biol. 15, cell.2020.04.008 525-530. doi:10.1016/j.cub.2005.01.043 Schmidt, T. M., Chen, S.-K. and Hattar, S. (2011). Intrinsically photosensitive Müller, M. and Holländer, H. (1988). A small population of retinal ganglion cells retinal ganglion cells: many subtypes, diverse functions. Trends Neurosci. 34, projecting to the retina of the other eye. Exp. Brain Res. 71, 611-617. doi:10.1007/ 572-580. doi:10.1016/j.tins.2011.07.001 BF00248754 Seabrook, T. A., El-Danaf, R. N., Krahe, T. E., Fox, M. A. and Guido, W. (2013). Müller, L. P. D. S., Dedek, K., Janssen-Bienhold, U., Meyer, A., Kreuzberg, Retinal input regulates the timing of corticogeniculate innervation. J. Neurosci. 33, M. M., Lorenz, S., Willecke, K. and Weiler, R. (2010). Expression and 10085-10097. doi:10.1523/JNEUROSCI.5271-12.2013 modulation of connexin 30.2, a novel gap junction protein in the mouse retina. Seabrook, T. A., Burbridge, T. J., Crair, M. C. and Huberman, A. D. (2017). Vis. Neurosci. 27, 91-101. doi:10.1017/S0952523810000131 Architecture, function, and assembly of the mouse visual system. Annu. Rev. Murcia-Belmonte, V., Coca, Y., Vegar, C., Negueruela, S., de Juan Romero, C., Neurosci. 40, 499-538. doi:10.1146/annurev-neuro-071714-033842 Valiño, A. J., Sala, S., DaSilva, R., Kania, A., Borrell, V. et al. (2019). A retino- Sekaran, S., Lupi, D., Jones, S. L., Sheely, C. J., Hattar, S., Yau, K.-W., Lucas, retinal projection guided by unc5c emerged in species with retinal waves. Curr. R. J., Foster, R. G. and Hankins, M. W. (2005). Melanopsin-dependent Biol. 29, 1149-1160.e4. doi:10.1016/j.cub.2019.02.052 photoreception provides earliest light detection in the mammalian retina. Curr. Nadal-Nicolás, F. M., Valiente-Soriano, F. J., Salinas-Navarro, M., Jiménez- Biol. 15, 1099-1107. doi:10.1016/j.cub.2005.05.053 López, M., Vidal-Sanz, M. and Agudo-Barriuso, M. (2015). Retino-retinal Sokhadze, G., Seabrook, T. A. and Guido, W. (2018). The absence of retinal input projection in juvenile and young adult rats and mice. Exp. Eye Res. 134, 47-52. disrupts the development of cholinergic brainstem projections in the mouse dorsal doi:10.1016/j.exer.2015.03.015 lateral geniculate nucleus. Neural Dev. 13, 27. doi:10.1186/s13064-018-0124-7 Neumann, C. J. and Nuesslein-Volhard, C. (2000). Patterning of the zebrafish Sondereker, K. B., Onyak, J. R., Islam, S. W., Ross, C. L. and Renna, J. M. retina by a wave of sonic hedgehog activity. Science 289, 2137-2139. doi:10. (2017). Melanopsin ganglion cell outer retinal dendrites: Morphologically distinct 1126/science.289.5487.2137 and asymmetrically distributed in the mouse retina. J. Comp. Neurol. 525, Newkirk, G. S., Hoon, M., Wong, R. O. and Detwiler, P. B. (2013). Inhibitory inputs 3653-3665. doi:10.1002/cne.24293 tune the light response properties of dopaminergic amacrine cells in mouse retina. Sondereker, K. B., Stabio, M. E. and Renna, J. M. (2020). Crosstalk: The diversity J. Neurophysiol. 110, 536-552. doi:10.1152/jn.00118.2013 of melanopsin ganglion cell types has begun to challenge the canonical divide Nguyen, M.-T. T., Vemaraju, S., Nayak, G., Odaka, Y., Buhr, E. D., Alonzo, N., between image-forming and non-image-forming vision. J. Comp. Neurol. 528, Tran, U., Batie, M., Upton, B. A., Darvas, M. et al. (2019). An opsin 5-dopamine 2044-2067. doi:10.1002/cne.24873 pathway mediates light-dependent vascular development in the eye. Nat. Cell Stacy, R. C., Demas, J., Burgess, R. W., Sanes, J. R. and Wong, R. O. L. (2005). Biol. 21, 420-429. doi:10.1038/s41556-019-0301-x Disruption and recovery of patterned retinal activity in the absence of Osterhout, J. A., Stafford, B. K., Nguyen, P. L., Yoshihara, Y. and Huberman, acetylcholine. J. Neurosci. 25, 9347-9357. doi:10.1523/JNEUROSCI.1800-05. A. D. (2015). Contactin-4 mediates axon-target specificity and functional 2005 development of the accessory optic system. Neuron 86, 985-999. doi:10.1016/j. Su, J., Charalambakis, N. E., Sabbagh, U., Somaiya, R. D., Monavarfeshani, A., neuron.2015.04.005 Guido, W. and Fox, M. A. (2020). Retinal inputs signal astrocytes to recruit O’Sullivan, M. L., Puñal, V. M., Kerstein, P. C., Brzezinski, J. A.,IV, Glaser, T., interneurons into visual thalamus. Proc. Natl. Acad. Sci. USA 117, 2671-2682.

Wright, K. M. and Kay, J. N. (2017). Astrocytes follow ganglion cell axons to doi:10.1073/pnas.1913053117 DEVELOPMENT

12 REVIEW Development (2020) 147, dev196535. doi:10.1242/dev.196535

Sun, Y. and Smith, L. E. H. (2018). Retinal vasculature in development and normal retinal organization depends on Sonic hedgehog signaling from ganglion diseases. Annu. Rev. Vis. Sci. 4, 101-122. doi:10.1146/annurev-vision-091517- cells. Nat. Neurosci. 5, 831-832. doi:10.1038/nn911 034018 Wang, Y., Dakubo, G. D., Thurig, S., Mazerolle, C. J. and Wallace, V. A. (2005). Sun, L. O., Brady, C. M., Cahill, H., Al-Khindi, T., Sakuta, H., Dhande, O. S., Retinal ganglion cell-derived sonic hedgehog locally controls proliferation and the Noda, M., Huberman, A. D., Nathans, J. and Kolodkin, A. L. (2015). Functional timing of RGC development in the embryonic mouse retina. Development 132, assembly of accessory optic system circuitry critical for compensatory eye 5103-5113. doi:10.1242/dev.02096 movements. Neuron 86, 971-984. doi:10.1016/j.neuron.2015.03.064 Watanabe, T. and Raff, M. C. (1990). Rod photoreceptor development in vitro: Syed, M. M., Lee, S., Zheng, J. and Zhou, Z. J. (2004). Stage-dependent dynamics intrinsic properties of proliferating neuroepithelial cells change as development and modulation of spontaneous waves in the developing rabbit retina. J. Physiol. proceeds in the rat retina. Neuron 4, 461-467. doi:10.1016/0896-6273(90)90058-N 560, 533-549. doi:10.1113/jphysiol.2004.066597 Watanabe, T. and Raff, M. C. (1992). Diffusible rod-promoting signals in the Tang, X., Tzekov, R. and Passaglia, C. L. (2016). Retinal cross talk in the developing rat retina. Development 114, 899-906. mammalian visual system. J. Neurophysiol. 115, 3018-3029. doi:10.1152/jn. Weiner, G. A., Shah, S. H., Angelopoulos, C. M., Bartakova, A. B., Pulido, R. S., 01137.2015 Murphy, A., Nudleman, E., Daneman, R. and Goldberg, J. L. (2019). Tao, C. and Zhang, X. (2016). Retinal proteoglycans act as cellular receptors for Cholinergic neural activity directs retinal layer-specific angiogenesis and blood basement membrane assembly to control astrocyte migration and angiogenesis. retinal barrier formation. Nat. Commun. 10, 2477. doi:10.1038/s41467-019- Cell Rep. 17, 1832-1844. doi:10.1016/j.celrep.2016.10.035 10219-8 Tennant, M., Bruce, S. R. and Beazley, L. D. (1993). Survival of ganglion cells Wilson, A. M. and Di Polo, A. (2012). Gene therapy for retinal ganglion cell which form the retino-retinal projection during optic nerve regeneration in the frog. neuroprotection in glaucoma. Gene Ther. 19, 127-136. doi:10.1038/gt.2011.142 Vis. Neurosci. 10, 681-686. doi:10.1017/S095252380000537X Wong, R. O. L. (1999). Retinal waves and visual system development. Annu. Rev. Thanos, S. (1999). Genesis, neurotrophin responsiveness, and apoptosis of a Neurosci. 22, 29-47. doi:10.1146/annurev.neuro.22.1.29 pronounced direct connection between the two eyes of the chick embryo: a natural Wu, F., Kaczynski, T. J., Sethuramanujam, S., Li, R., Jain, V., Slaughter, M. and error or a meaningful developmental event? J. Neurosci. 19, 3900-3917. doi:10. Mu, X. (2015). Two transcription factors, Pou4f2 and Isl1, are sufficient to specify 1523/JNEUROSCI.19-10-03900.1999 the retinal ganglion cell fate. Proc. Natl. Acad. Sci. 112, E1559-E1568. doi:10. Tóth, P. and Strznicky, C. (1989). Retino-retinal projections in three anuran 1073/pnas.1421535112 species. Neurosci. Lett. 104, 43-47. doi:10.1016/0304-3940(89)90326-1 Yamagata, M. and Sanes, J. R. (2008). Dscam and Sidekick proteins direct lamina- Tran, N. M., Shekhar, K., Whitney, I. E., Jacobi, A., Benhar, I., Hong, G., Yan, W., specific synaptic connections in vertebrate retina. Nature 451, 465-469. doi:10. Adiconis, X., Arnold, M. E., Lee, J. M. et al. (2019). Single-cell profiles of retinal 1038/nature06469 ganglion cells differing in resilience to injury reveal neuroprotective genes. Neuron Yamagata, M., Weiner, J. A. and Sanes, J. R. (2002). Sidekicks: synaptic adhesion 104, 1039-1055.e12. doi:10.1016/j.neuron.2019.11.006 molecules that promote lamina-specific connectivity in the retina. Cell 110, Trimarchi, J. M., Stadler, M. B. and Cepko, C. L. (2008). Individual retinal 649-660. doi:10.1016/S0092-8674(02)00910-8 progenitor cells display extensive heterogeneity of gene expression. PLoS ONE 3, Yamaguchi, T. P., Dumont, D. J., Conlon, R. A., Breitman, M. L. and Rossant, J. e1588. doi:10.1371/journal.pone.0001588 (1993). flk-1, an flt-related receptor tyrosine kinase is an early marker for Tufford, A. R., Onyak, J. R., Sondereker, K. B., Lucas, J. A., Earley, A. M., Mattar, endothelial cell precursors. Development 118, 489-498. P., Hattar, S., Schmidt, T. M., Renna, J. M. and Cayouette, M. (2018). Yang, X. and Cepko, C. L. (1996). Flk-1, a receptor for vascular endothelial growth Melanopsin retinal ganglion cells regulate cone photoreceptor lamination in the factor (VEGF), is expressed by retinal progenitor cells. J. Neurosci. 16, mouse retina. Cell Rep. 23, 2416-2428. doi:10.1016/j.celrep.2018.04.086 6089-6099. doi:10.1523/JNEUROSCI.16-19-06089.1996 Turner, D. L., Snyder, E. Y. and Cepko, C. L. (1990). Lineage-independent Young, R. W. (1985). Cell differentiation in the retina of the mouse. Anat. Rec. 212, determination of cell type in the embryonic mouse retina. Neuron 4, 833-845. 199-205. doi:10.1002/ar.1092120215 doi:10.1016/0896-6273(90)90136-4 Zhang, X. M. and Yang, X. J. (2001). Regulation of retinal ganglion cell production Usui, Y., Westenskow, P. D., Kurihara, T., Aguilar, E., Sakimoto, S., Paris, L. P., by Sonic hedgehog. Development 128, 943-957. Wittgrove, C., Feitelberg, D., Friedlander, M. S. H., Moreno, S. K. et al. (2015). Zhang, D.-Q., Wong, K. Y., Sollars, P. J., Berson, D. M., Pickard, G. E. and Neurovascular crosstalk between interneurons and capillaries is required for McMahon, D. G. (2008). Intraretinal signaling by ganglion cell photoreceptors to vision. J. Clin. Invest. 125, 2335-2346. doi:10.1172/JCI80297 dopaminergic amacrine neurons. Proc. Natl. Acad. Sci. USA 105, 14181-14186. Völgyi, B., Chheda, S. and Bloomfield, S. A. (2009). Tracer coupling patterns of doi:10.1073/pnas.0803893105 the ganglion cell subtypes in the mouse retina. J. Comp. Neurol. 512, 664-687. Zhang, D.-Q., Belenky, M. A., Sollars, P. J., Pickard, G. E. and McMahon, D. G. doi:10.1002/cne.21912 (2012). Melanopsin mediates retrograde visual signaling in the retina. PLoS ONE Waid, D. K. and McLoon, S. C. (1998). Ganglion cells influence the fate of dividing 7, e42647. doi:10.1371/journal.pone.0042647 retinal cells in culture. Development 125, 1059-1066. Zlomuzica, A., Reichinnek, S., Maxeiner, S., Both, M., May, E., Wörsdörfer, P., Wallace, V. A. and Raff, M. C. (1999). A role for Sonic hedgehog in axon-to- Draguhn, A., Willecke, K. and Dere, E. (2010). Deletion of connexin45 in mouse astrocyte signalling in the rodent optic nerve. Development 126, 2901-2909. neurons disrupts one-trial object recognition and alters kainate-induced γ- Wang, Y. P., Dakubo, G., Howley, P., Campsall, K. D., Mazarolle, C. J., Shiga, oscillations in the hippocampus. Physiol. Behav. 101, 245-253. doi:10.1016/j. S. A., Lewis, P. M., McMahon, A. P. and Wallace, V. A. (2002). Development of physbeh.2010.05.007 DEVELOPMENT