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WIREs Dev Biol
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Molecular mechanisms regulating synaptic specificity and retinal circuit formation

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Abstract The central nervous system (CNS) is composed of precisely assembled circuits which support a variety of physiological functions and behaviors. These circuits include multiple subtypes of neurons with unique morphologies, electrical properties, and molecular identities. How these component parts are precisely wired‐up has been a topic of great interest to the field of developmental neurobiology and has implications for our understanding of the etiology of many neurological disorders and mental illnesses. To date, many molecules involved in synaptic choice and specificity have been identified, including members of several families of cell‐adhesion molecules (CAMs), which are cell‐surface molecules that mediate cell‐cell contacts and subsequent intracellular signaling. One favored hypothesis is that unique expression patterns of CAMs define specific neuronal subtype populations and determine compatible pre‐ and postsynaptic neuronal partners based on the expression of these unique CAMs. The mouse retina has served as a beautiful model for investigations into mammalian CAM interactions due to its well‐defined neuronal subtypes and distinct circuits. Moreover, the retina is readily amenable to visualization of circuit organization and electrophysiological measurement of circuit function. The advent of recent genetic, genomic, and imaging technologies has opened the field up to large‐scale, unbiased approaches for identification of new molecular determinants of synaptic specificity. Thus, building on the foundation of work reviewed here, we can expect rapid expansion of the field, harnessing the mouse retina as a model to understand the molecular basis for synaptic specificity and functional circuit assembly. This article is categorized under: Nervous System Development > Vertebrates: General Principles Nervous System Development > Vertebrates: Regional Development
Synapse formation in the OPL. Wildtype rod photoreceptors (PRs) and bipolar cells (BCs) are depicted on the left. Cao et al. identified ELFN1 as a rod‐expressed, direct binding partner of ON bipolar cell MGLUR6. Loss of ELFN1 prevents proper synapse formation between these two neurons (right)
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Laminar targeting in the OPL. Wildtype horizontal cells (HCs) and photoreceptors (PRs) are depicted on the left. Matsuoka et al. found that HCs express SEMA6A and its receptor PLEXA4, and that loss of either results in ectopic neurites in the outer nuclear layer. Ribic et al., found that loss of SYNCAM1 results in a very similar HC dendritic morphological defect (center). Sarin et al. found that rod bipolar cell (BC) expression of WNT ligands signal to rods through the receptor RYK to mediate synapse formation between these cell types. Loss of these molecules results in ectopic plexiform formation, composed of neurites from PRs, BCs, and HCs (right)
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Diagram of neuron types in the outer retina. Rod (turquoise) and cone (yellow) photoreceptors (PRs) receive light input and signal to postsynaptic horizontal cells (HCs) (pink) and bipolar cells (BCS) (green)
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Synapse formation in the IPL. Wildtype retinal ganglion cells (RGCs) and amacrine cells (ACs) are depicted on the left of each panel. Krishnaswamy et al. found that SDK‐2 is localized at the synapses between VG3 ACs and W3B RGCs, and that loss of SDK‐2 prevents proper synapse formation between these two neurons (left). Duan et al. found that only the combined loss, but not the loss of one or two, of CDH6, CDH9, and CDH10 results in loss of tight cofasciculation between ON/OFF direction‐selective ganglion cells (ooDSGCs) and starburst ACs (SACs) (right)
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Laminar targeting in the IPL. Wildtype retinal ganglion cells (RGCs), bipolar cells (BCs), and starburst amacrine cells (SACs) are depicted on the left of each panel. Duan et al. found that a subtype of OFF BC selectively expresses CDH8, whereas a subtype of ON BC selectively expresses CDH9. They showed that ectopic expression of either of these molecules is sufficient to instruct the divergent laminar targeting (left). Sun et al. showed that loss of SEMA6A‐PLEXA2 results in loss of segregation between ON and OFF SACs (right)
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Diagram of neuron types in the inner retina. OFF bipolar cells (BCs) (light green), ON BCs (dark green), starburst amacrine cells (SACs) (orange), VG3 amacrine cells (VG3 ACs)(red), W3B retinal ganglion cells (W3B RGCs) (dark blue), and ON/OFF direction‐selective ganglion cells (ooDSGCs) (light blue)
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Synaptic maintenance in the OPL. Wildtype horizontal cells (HCs), rod photoreceptors (PRs), and bipolar cells (BCs) are depicted on the left. Age‐related loss of synaptic integrity results in ectopic neurites and synapses in the outer nuclear layer, due to retraction of rod axons. Samuel et al. found that loss of LKB1‐AMPK signaling induces similar changes in the retinas of young mice, implicating these molecules in the maintenance of normal synaptic architecture in the outer plexiform layer (right)
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