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Retinogenesis of the Human Fetal Retina: an Apical Polarity Perspective

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Retinogenesis of the Human Fetal Retina: an Apical Polarity Perspective G C A T T A C G G C A T genes Review Retinogenesis of the Human Fetal Retina: An Apical Polarity Perspective Peter M.J. Quinn 1 and Jan Wijnholds 1,2,* 1 Department of Ophthalmology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; [email protected] 2 The Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, 1105 BA Amsterdam, The Netherlands * Correspondence: [email protected]; Tel.: +31-71-526-9269 Received: 21 August 2019; Accepted: 26 November 2019; Published: 29 November 2019 Abstract: The Crumbs complex has prominent roles in the control of apical cell polarity, in the coupling of cell density sensing to downstream cell signaling pathways, and in regulating junctional structures and cell adhesion. The Crumbs complex acts as a conductor orchestrating multiple downstream signaling pathways in epithelial and neuronal tissue development. These pathways lead to the regulation of cell size, cell fate, cell self-renewal, proliferation, differentiation, migration, mitosis, and apoptosis. In retinogenesis, these are all pivotal processes with important roles for the Crumbs complex to maintain proper spatiotemporal cell processes. Loss of Crumbs function in the retina results in loss of the stratified appearance resulting in retinal degeneration and loss of visual function. In this review, we begin by discussing the physiology of vision. We continue by outlining the processes of retinogenesis and how well this is recapitulated between the human fetal retina and human embryonic stem cell (ESC) or induced pluripotent stem cell (iPSC)-derived retinal organoids. Additionally, we discuss the functionality of in utero and preterm human fetal retina and the current level of functionality as detected in human stem cell-derived organoids. We discuss the roles of apical-basal cell polarity in retinogenesis with a focus on Leber congenital amaurosis which leads to blindness shortly after birth. Finally, we discuss Crumbs homolog (CRB)-based gene augmentation. Keywords: apical polarity; crumbs complex; fetal retina; PAR complex; retinal organoids; retinogenesis; gene augmentation; adeno-associated virus (AAV); Leber congenital amaurosis 1. The Physiology of Vision Vision is perhaps the most dominant sense in daily life and both non-correctable unilateral and bilateral vision loss severely impact the quality of life [1]. Vision begins with the processing of light, which is electromagnetic radiation that travels as waves (Figure1A). Light waves, as with all waves, can be characterized by their wavelength (distance between wave peaks), frequency (number of wavelengths within a time period), and amplitude (the height of each peak or depth of each trough). Visible light is a narrow group of wavelengths between approximately 400 nm and 760 nm which we interpret as a spectrum of different colors (Figure1B) [2]. Light can be reflected (bounce of a surface), absorbed (transfer of energy to a surface), or refracted (bending of light between two mediums) (Figure1C). Genes 2019, 10, 987; doi:10.3390/genes10120987 www.mdpi.com/journal/genes Genes 2019, 10, 987 2 of 40 Genes 2019, 10, 987 2 of 38 Figure 1. Transmission of light. (A) Light is electromagnetic radiation that travels as waves consisting of Figure 1. Transmission of light. (A) Light is electromagnetic radiation that travels as waves consisting perpendicular oscillating electric and magnetic fields. (B) Visible light is a narrow group of wavelengths of perpendicular oscillating electric and magnetic fields. (B) Visible light is a narrow group of between approximately 400 nm (short wavelength) and 760 nm (long wavelength) which we interpret aswavelengths a spectrum between of different approximately colors. Wavelengths 400 nm (short outside wavelength) this range and are 760 not nm visible (long to wavelength) humans. (C) which Light canwe interpret be reflected, as absorbeda spectrum and of refracted. different colors. Wavelengths outside this range are not visible to humans. (C) Light can be reflected, absorbed and refracted. When light first enters the eye, it is refracted by the cornea through the pupil, whose size is controlledWhen by light the first iris. Theenters iris, the the eye, colored it is partrefracted of the by eye, the controls cornea the through amount the of lightpupil, entering whose thesize eye is whilecontrolled the lens by focusesthe iris. theThe light iris, throughthe colored the vitreouspart of the humor eye, and controls on to the proximalamount of surface light entering of the retina the (Figureeye while2A). the The lens adult focuses retina the consists light through of one glial the vitr celleous type, humor the Müller and glialon to cells, the proximal and six major surface types of the of neurons,retina (Figure the rod 2A). and The cone adult photoreceptors, retina consists bipolar of one cells,glial cell amacrine type, the cells, Müller horizontal glial cells, cells, and and six ganglion major cellstypes (Figure of neurons,2B). Their the rod cell and bodies cone are photoreceptors, distributed across bipolar three cells, nuclear amacrine layers, cells, the horizontal outer nuclear cells, layer and (ONL),ganglion inner cells nuclear (Figure layer 2B). (INL), Their and cell ganglion bodies cellare layerdistributed (GCL). Twoacross synaptic three layers,nuclear the layers, outer plexiformthe outer layernuclear (OPL) layer and (ONL), inner inner plexiform nuclear layer layer (IPL), (INL), contain and theganglion axonal cell and layer dendritic (GCL). processes Two synaptic of the cells layers, [3]. Whereasthe outer thereplexiform is one layer type (OPL) of rod and photoreceptor, inner plexiform there layer are various (IPL), contain subtypes the of axonal cone photoreceptor,and dendritic bipolar,processes amacrine, of the cells horizontal, [3]. Whereas and ganglion there is one cells type that diofff roder in photoreceptor, their functional there roles are and various morphology subtypes [4]. Besidesof cone photoreceptor, Müller glial cells bipolar, there are amacrine, two other horizontal, glial cell typesand ganglion that serve cells to maintainthat differ retinal in their homeostasis, functional theroles astrocytes and morphology and resident [4]. microgliaBesides Müller [5]. Light glial must cells be there channelled are two through other glial the cell retina types and that absorbed serve byto itsmaintain three light retinal responsive homeostasis, cells: the the rodastrocytes and cone and photoreceptors resident microglia and the[5]. intrinsically-photosensitive Light must be channelled retinalthrough ganglion the retina cells and (ipRGCs). absorbed The bymammalian its three light retina responsive contains cells: various the opsinrod and proteins cone photoreceptors involved in the photoreceptionand the intrinsically-photosensitive synchronisation of circadian retinal ganglion rhythms cells (photoentrainment). (ipRGCs). The mammalian These are theretina cone contains opsins (Mvarious/LWS, opsin red/green proteins opsin; involved SWS1, blue in opsin)the photor responsibleeception for synchronisation high visual acuity, of resolution, circadian andrhythms color vision(photoentrainment). (photopic vision), These and are rod the opsin cone (RH1, opsins Rhodopsin) (M/LWS, responsible red/green for opsin; dim lightSWS1, vision blue (scotopic opsin) vision)responsible andipRGCs for high opsin visual (OPN4, acuity, Melanopsin) resolution, and responsible color vision for synchronisation (photopic vision), of the and circadian rod opsin rhythms (RH1, andRhodopsin) ambient responsible light perception for dim [6– light9]. The vision cones (scoto are lesspic vision) sensitive and to ipRGCs light and op rodssin (OPN4, are more Melanopsin) sensitive to lightresponsible and are for also synchronisation used together under of the intermediated circadian rhythms light conditions and ambient (mesopic light vision) perception [10]. Most [6–9]. forms The ofcones inherited are less retinal sensitive disease to light negatively and rods aff areect more the function sensitive of to photoreceptors, light and are al resultingso used together in progressive under lossintermediated of rod and /lightor cone conditions photoreceptors. (mesopic Müller vision) glial [10]. cells Most mediate forms the of channelling inherited ofretinal light throughdisease thenegatively retina towardsaffect the the function photoreceptors of photoreceptors, [11,12]. Müller resulting glial cellsin progressive can channel loss di ffoferent rod wavelengthsand/or cone ofphotoreceptors. light to specific Müller subsets glial of photoreceptorscells mediate the to chan optimisenelling day of vision light [through13]. The the visual retina pigments towards of the photoreceptors [11,12]. contain Müller an opsin glial protein cells can covalently channel linkeddifferent to wavelengths the chromophore of light 11- tocis specific-retinal. subsets Upon theof photoreceptors absorption of to a photonoptimise 11- daycis -retinalvision [13]. becomes The visual isomerised pigments to all-of thetrans photoreceptors-retinal, this leads contain to an activatedopsin protein opsin covalently intermediate linked (metarhodopsin to the chromophore II, rods; Meta-II,11-cis-retinal. cones). Upon This the active absorption intermediate of a leadsphoton to triggering11-cis-retinal of abecomes transduction isomerised cascade to resultingall-trans-retinal, in hyperpolarisation this leads to ofan the activated photoreceptors, opsin intermediate due to the (metarhodopsin II, rods; Meta-II,
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