An extracellular biochemical screen reveals that FLRTs and Unc5s mediate neuronal subtype recognition in the retina

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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 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 that a single molecular mechanism may have been co-opted by synaptic partners to ensure joint laminar restriction.

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Jasper J Visser

Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
Yolanda Cheng

Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
Steven C Perry

Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
Andrew Benjamin Chastain

Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
Bayan Parsa

Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
Shatha S Masri

Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

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The authors declare that no competing interests exist.
Thomas A Ray

Departments of Neurobiology and Opthalmology, Duke University School of Medicine, Durham, United States

Competing interests
The authors declare that no competing interests exist.
Jeremy N Kay

Departments of Neurobiology and Opthalmology, Duke University School of Medicine, Durham, United States

Competing interests
The authors declare that no competing interests exist.
Woj M Wojtowicz

Molecular and Cell Biology, University of California Berkeley, Berkeley, United States

For correspondence
woj.wojtowicz@gmail.com

Competing interests
The authors declare that no competing interests exist.

Ethics

Animal experimentation: All animal procedures were approved by the University of California, Berkeley (Office of Laboratory Animal Care (OLAC) protocol #R308) and they conformed to the National Institutes of Health Guide for the Care and Use of Laboratory Animals, the Public Health Service Policy and the Society for Neuroscience Policy on the Use of Animals in Neuroscience Research.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.