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Intracellular Trafficking in Drosophila Visual System Development: a Basis

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Intracellular Trafficking in Drosophila Visual System Development: a Basis Intracellular Trafficking in Drosophila Visual System Development: A Basis for Pattern Formation Through Simple Mechanisms Chih-Chiang Chan, Daniel Epstein, P. Robin Hiesinger Department of Physiology and Green Center for Systems Biology, UT Southwestern Medical Center, Dallas, Texas Received 30 December 2010; accepted 17 June 2011 ABSTRACT: Intracellular trafficking underlies cel- apse formation signals. Yet, the Drosophila visual system lular functions ranging from membrane remodeling to provides some of the most striking examples for the receptor activation. During multicellular organ develop- regulatory role of intracellular trafficking during multi- ment, these basic cell biological functions are required as cellular organ development. In this review we will first both passive machinery and active signaling regulators. highlight the experimental and conceptual advances that Exocytosis, endocytosis, and recycling of several key motivate the study of intracellular trafficking during signaling receptors have long been known to actively reg- Drosophila visual system development. We will then illu- ulate morphogenesis and pattern formation during Dro- minate the development of the eye, the eye-to-brain con- sophila eye development. Hence, intracellular membrane nectivity map and the optic lobe from the perspective of trafficking not only sets the cell biological stage for recep- cell biological dynamics. Finally, we provide a conceptual tor-mediated signaling but also actively controls signaling framework that seeks to explain how the interplay of sim- through spatiotemporally regulated receptor localization. ple genetically encoded intracellular trafficking events In contrast to eye development, the role of intracellular governs the seemingly complex cellular behaviors, which trafficking for the establishment of the eye-to-brain con- in turn determine the developmental product. ' 2011 nectivity map has only recently received more attention. Wiley Periodicals, Inc. Develop Neurobiol 71: 1227–1245, 2011 It is still poorly understood how guidance receptors are Keywords: receptor sorting; degradation; signaling; spatiotemporally regulated to serve as meaningful syn- neurogenetics; optic lobe INTRODUCTION system to study basic questions of tissue morphogen- esis, pattern formation, and underlying signaling The Drosophila visual system comprises of the eyes mechanisms for decades (Meinertzhagen and Hanson, and optic lobes. The eye has been a powerful model 1993; Wolff and Ready, 1993). This is partly due to the beauty and crystalline organization of both the P.R.H. is a Eugene McDermott Scholar in Biomedical Research eye and the underlying brain regions, which greatly at UT Southwestern Medical Center. facilitate the discovery and study of pattern forma- Correspondence to: P.R. Hiesinger (robin.hiesinger@ tion. Maybe even more importantly, the Drosophila utsouthwestern.edu). Contract grant sponsor: Welch Foundation; contract grant num- eye has very practical experimental advantages: the ber: I-1657. visual system is not required for viability under labo- Contract grant sponsor: Cancer Prevention Research Institute of ratory conditions, and it is easily amenable to genetic Texas (CPRIT). Contract grant sponsor: National Institute of Health (NEI/NIH); and other experimental manipulations. Consequently, contract grant number: RO1018884. many discoveries of basic developmental mecha- ' 2011 Wiley Periodicals, Inc. nisms were made possible by studies of Drosophila Published online 28 June 2011 in Wiley Online Library (wileyonlinelibrary.com). visual system development, including the interplay of DOI 10.1002/dneu.20940 transcriptional regulation and cell biology during eye 1227 1228 Chan et al. development (see Kumar, 2011; Rister and Desplan, mental signaling pathways, such as epidermal growth 2011), and the discovery and characterization of key factor receptor (EGFR) and Notch (Eun et al., 2007; proteins in several signal transduction pathways Iyadurai et al., 2008). [reviewed in (Dickson and Hafen, 1993)]. The second major technological improvement The optic lobe comprises roughly half of the derives from dramatic advances of imaging tech- Drosophila brain. It receives direct input from the nology in recent years. In light of the ability to photoreceptors in the first optic ganglion, the lam- non-invasively monitor and \virtually dissect" ina. The layer-specific projections of photoreceptor intact specimens, the small size of Drosophila has axons in the optic lobe and the formation of a vis- become a considerable advantage. The Drosophila ual map in the lamina in particular have yielded visual system in particular is amenable to the important insights into the problem of brain wiring most advanced modern imaging in toto, i.e., a and synaptic specification (Clandinin and Feldheim, complete eye–brain complex from a developing 2009; Sanes and Zipursky, 2010). While the role fly fits under high-resolution laser scanning and of intracellular trafficking in the signaling events other live imaging microscopes (Williamson and that lead to pattern formation in the eye has been Hiesinger, 2010). In combination with the genetic studied for a long time, the investigation of the techniques mentioned above, almost any transgenic role of intracellular trafficking as part of the brain animal can be generated where individual cells, wiring program has only recently become a intracellular compartments, or proteins are labeled research focus. This is certainly at least partly due with any kind of fluorophore to image cellular to newly developed techniques that have only been and subcellular biology in vivo in a developing developed or become widely available in recent eye–brain complex. It is arguably this combination years. The developments in two areas are most im- of technological advantages that allows the study portant and will be discussed below: first, molecu- of intracellular trafficking in the development and lar genetic manipulation of the visual system in function of specialized neurons in their in vivo vivo and second, the imaging of the intact visual and in situ context in ways that were previously system in vivo. only possible in cell culture. In light of these two The classical advantage of the visual system as a major technological advances, it is maybe of little model for genetic manipulation has received a major surprise that the last few years have yielded rich boost with the development of techniques to render new insights into the cell biology, and membrane mutations homozygous only in photoreceptors and trafficking in particular, of the developing visual visual interneurons in otherwise heterozygous ani- system. mals (Stowers and Schwarz, 1999; Newsome et al., In addition to technical challenges, the role of in- 2000; Chotard et al., 2005). In combination with tracellular trafficking has long posed a conceptual other tricks from the Drosophila tool box, these challenge for the study of neural circuit formation methods allow the easy generation of transgenic flies and synapse specification. While it is clear that mem- in which a subset of photoreceptor cells can be ren- brane trafficking and other cell biological machinery dered mutant and negatively or positively labeled are required for specific recognition and signaling with any combination of fluorescent proteins. In addi- events (i.e., play a permissive role in the developmen- tion, the mutant and/or control cells can be tal program), it is more difficult to envision an active engineered to express additional transgenes for experi- role of intracellular trafficking in the actual synapse ments ranging from simple genetic rescue, to genetic specification process (i.e., an instructive role). A sim- interaction and structure function studies of individual ilar debate has accompanied the study of cytoskeletal proteins—all in otherwise wild type (heterozygous) dynamics in axon pathfinding for many years flies. Several genetics screens in Drosophila have been (Dickson, 2001). It is maybe a little bit surprising that performed to identify novel components that regulate so little attention has been given to intracellular traf- intracellular trafficking in the eye. Abnormal eye pig- ficking as part of the \brain making program," given mentation can serve as readout for genes that regulate that examples for key roles of receptor trafficking in protein delivery to lysosomes (Lloyd et al., 1998). For signaling events underlying developmental processes example, acinus (dacn) has been identified as a regula- abound. Here, we will not provide a complete review tor of endosomal transport and autophagosomal matu- of all components of intracellular trafficking and their ration (Haberman et al., 2010). Genetic modifier roles in signaling in general; this topic is covered in screens in the eye have also led to unbiased discoveries comprehensive and highly recommended reviews of trafficking components for general trafficking ma- elsewhere (Polo and Di Fiore, 2006; von Zastrow and chinery (Simonsen et al., 2007), as well as for develop- Sorkin, 2007; Sorkin and von Zastrow, 2009). Developmental Neurobiology Intracellular Trafficking in Drosophila 1229 Figure 1 Feedback between intracellular trafficking and signaling from the viewpoint of a sig- naling receptor. Intracellular trafficking pathways are shown with black arrows; possible signaling effects with red arrows. Note that intracellular trafficking can directly regulate signaling via sorting, endocytosis, and exocytosis of receptors and signaling molecules. Furthermore, the signaling
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