Abstract
In the inner plexiform layer (IPL) of the mouse retina, ~70 neuronal subtypes organize their neurites into an intricate laminar structure that underlies visual processing. To find recognition proteins involved in lamination, we utilized microarray data from 13 subtypes to identify differentially-expressed extracellular proteins and performed a high-throughput biochemical screen. We identified ~50 previously-unknown receptor-ligand pairs, including new interactions among members of the FLRT and Unc5 families. These proteins show laminar-restricted IPL localization and induce attraction and/or repulsion of retinal neurites in culture, placing them in an ideal position to mediate laminar targeting. Consistent with a repulsive role in arbor lamination, we observed complementary expression patterns for one interaction pair, FLRT2-Unc5C, in vivo. Starburst amacrine cells and their synaptic partners, ON-OFF direction-selective ganglion cells, express FLRT2 and are repelled by Unc5C. These data suggest a single molecular mechanism may have been co-opted by synaptic partners to ensure joint laminar restriction.
Highlights
In many regions of the nervous system, neurons and their arbors are organized in parallel layers
We reasoned that good candidates for mediating neuronal subtype-specific recognition in the inner plexiform layer (IPL) are cell surface and secreted proteins that are differentially expressed in different subtypes of amacrine, bipolar and retinal ganglion cells
As no published list of all cell surface and secreted proteins in the mouse genome exists, we first predicted all of the cell surface and secreted proteins using a variety of bioinformatics approaches
Summary
In many regions of the nervous system, neurons and their arbors are organized in parallel layers. This organization provides an architectural framework that facilitates the assembly of neural circuits in a stereotyped fashion, a crucial feature that underlies function of the structure. Laminated structures are composed of multiple different classes and subtypes of neurons that form distinct connections in specific stratified layers. The cell bodies and/or neurites of these different neuronal subtypes become restricted to one or more distinct strata. Costratification of arbors promotes synaptic specificity by placing appropriate synaptic partners in close proximity to one another. As such, understanding how lamination occurs is essential to uncovering the molecular basis of how highly-specific neural circuits form
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