Abstract
Processes of >100 types of interneurons (bipolar and amacrine cells) and projection neurons (retinal ganglion cells, RGCs) form specific and stereotyped patterns of connections in the inner plexiform layer (IPL) of the mouse retina. Four closely related homophilic immunoglobulin superfamily recognition molecules (Sidekick [Sdk] 1, Sdk 2, Dscam, and DscamL1) have been shown to play roles in patterning neuronal arbors and connections in chick retina, and all but Sdk1 have been shown to play related roles in mice. Here, we compare patterns of Sdk1 and Sdk2 expression in mouse retina and use genetic methods to assess roles of Sdk1. In adult retina, 3 neuronal types express sdk1 but not sdk2 at detectable levels, 5 express sdk2 but not sdk1 and 3 express both. Patterns of gene expression and protein localization at or near synapses are established during the first postnatal week. Dendrites of amacrine cells and RGCs that express sdk1 but not sdk2 arborize in the same narrow stratum in the center of the IPL. In the absence of Sdk1, this laminar restriction is degraded. Overexpression of sdk1 in developing cells that normally express sdk2 reorients their dendrites to resemble those of endogenously Sdk1-positive cells, indicating that Sdk1 plays an instructive role in patterning the IPL. Sdk1 fails to affect arbors when introduced after they are mature, suggesting that it is required to form but not maintain laminar restrictions. The effect of ectopically expressed sdk1 requires the presence of endogenous Sdk1, suggesting that the effect requires homophilic interactions among Sdk1-positive neurites. Together with previous results on Sdk2, Dscam, DscamL1, as well as the related Contactins, our results support the idea that an elaborate immunoglobulin superfamily code plays a prominent role in establishing neural circuits in the retina by means of tightly regulated cell type-specific expression and homophilically restricted intercellular interactions.
Highlights
Over the past decade, the mouse retina has emerged as a valuable model for investigating how “hard-wired” neural circuits are assembled
We found that sdk2 is expressed by restricted subsets of retinal neurons, including an unusual glutamatergic amacrine interneuron called VGlut3positive amacrine cells (VG3-ACs) (Haverkamp and Wässle, 2004; Johnson et al, 2004; Grimes et al, 2011) and an RGC type called W3B, which has the unusual property of responding when the timing of the movement of a small object differs from that of the background, but not when they coincide (Kim et al, 2010, 2015; Zhang et al, 2012; Lee et al, 2014; Krishnaswamy et al, 2015)
We showed that VG3-ACs synapse on W3B-RGCs, that VG3 input is essential for W3B-RGC function, that Sdk2 is required for restriction of VG3-AC and W3B-RGC processes to appropriate strata, and that the number and strength of functional connections between VG3-ACs and W3B-RGCs are dramatically reduced in the absence of Sdk2 (Krishnaswamy et al, 2015)
Summary
The mouse retina has emerged as a valuable model for investigating how “hard-wired” neural circuits are assembled. The specific and stereotyped patterns of these connections endow each RGC type with selective sensitivity to specific visual features, such as motion in a particular direction, edges, or color contrasts (reviewed in Masland, 2012; Sanes and Masland, 2015) Analysis of these circuits has implicated a variety of recognition molecules in the cell-cell interactions that establish them; they include members of the immunoglobulin and cadherin superfamilies, the semaphorins and plexins, and others (e.g., Fuerst et al, 2008, 2009, 2012; Matsuoka et al, 2011; Kay et al, 2012; Lefebvre et al, 2012; Sun et al, 2013; Duan et al, 2014, 2018; Krishnaswamy et al, 2015; Peng et al, 2017; Liu et al, 2018; reviewed in Zhang et al, 2017). Since all of these molecules are expressed by neuronal subsets throughout the brain, insights obtained in studies of the retina are likely to be relevant to the central nervous system generally
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