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Jeremy N Kay, Megan Stogsdill; Starburst amacrine cells orchestrate assembly of retinal direction-selective circuitry. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1337.
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© ARVO (1962-2015); The Authors (2016-present)
During retinal development, over 70 different neuron types form circuits devoted to specific visual processing tasks. Differentiating neurons grow axons and dendrites into the inner plexiform layer (IPL), where neurons that share a role in visual processing find each other and establish specific contacts. The mechanisms underlying circuit-specific arbor recognition and recruitment remain unclear. To probe these mechanisms we use the direction-selective (DS) circuit of mouse retina as a model, because its constituent cell types are known and can be manipulated in genetically modified mice. The main DS circuit cell types - DS ganglion cells (DSGCs), starburst amacrine cells (SACs), and bipolar cells of types 5 and 7 - form selective contacts in specific sublayers of the IPL. This anatomy suggests that attractive cues, originating from one or more of these three cell classes, might recruit DS circuit axons and dendrites in order to assemble the circuit. SACs are particularly well positioned to act as circuit organizers, since they stratify in the IPL before other DS cell types. Here we tested the hypothesis that SACs provide circuit-organizing cues to DSGCs and bipolar cells.
To ask whether SACs recruit their DS circuit partners, we devised a genetic strategy to selectively perturb SAC IPL projections. In mouse Megf10 mutants, SAC somata fail to form a mosaic; instead, cell bodies are randomly positioned. We found that local SAC cell body density dictates density of SAC dendrites in the IPL: Cell body clumps produce dendrite clumps that often overflow their correct IPL stratum, whereas cell body gaps create IPL voids never innervated by SACs. If SACs guide DS circuit assembly, then DSGCs and Type 5/7 bipolar cells should make IPL innervation errors in Megf10 mutants that mirror those made by SACs.
We found that SACs provide instructive cues for DSGC dendrite growth: Dendrites are recruited to ectopic starburst IPL clumps in Megf10 mutants, and fail to enter starburst IPL gaps. By contrast, SACs are not required for IPL innervation by DS circuit bipolar cells. Instead, quite unexpectedly, we found that SACs provide repulsive cues that specify the precise IPL positions of Type 5 and 7 axons.
These results demonstrate that SACs orchestrate DS circuit assembly by exerting distinct cell-biological effects on their circuit partners.
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