Formation of retinal direction-selective circuitry initiated by starburst amacrine cell homotypic contact
Abstract
A common strategy by which developing neurons locate their synaptic partners is through projections to circuit-specific neuropil sublayers. Once established, sublayers serve as a substrate for selective synapse formation, but how sublayers arise during neurodevelopment remains unknown. Here we identify the earliest events that initiate formation of the direction-selective circuit in the inner plexiform layer of mouse retina. We demonstrate that radially-migrating newborn starburst amacrine cells establish homotypic contacts on arrival at the inner retina. These contacts, mediated by the cell-surface protein MEGF10, trigger neuropil innervation resulting in generation of two sublayers comprising starburst-cell dendrites. This dendritic scaffold then recruits projections from circuit partners. Abolishing MEGF10-mediated contacts profoundly delays and ultimately disrupts sublayer formation, leading to broader direction tuning and weaker direction-selectivity in retinal ganglion cells. Our findings reveal a mechanism by which differentiating neurons transition from migratory to mature morphology, and highlight this mechanism's importance in forming circuit-specific sublayers.
Article and author information
Author details
Funding
National Eye Institute (EY024694)
- Jeremy N Kay
National Eye Institute (EY5722 to Duke University)
- Thomas A Ray
- Suva Roy
- Christopher Kozlowski
- Jingjing Wang
- Jon Cafaro
- Samuel W Hulbert
- Greg D Field
- Jeremy N Kay
Pew Charitable Trusts
- Jeremy N Kay
E. Matilda Ziegler Foundation for the Blind
- Jeremy N Kay
McKnight Endowment Fund for Neuroscience
- Jeremy N Kay
Alfred P. Sloan Foundation
- Jeremy N Kay
Whitehall Foundation
- Greg D Field
Research to Prevent Blindness (Unrestricted grant to Duke University)
- Thomas A Ray
- Suva Roy
- Christopher Kozlowski
- Jingjing Wang
- Jon Cafaro
- Greg D Field
- Jeremy N Kay
National Eye Institute (EY026344)
- Thomas A Ray
National Eye Institute (EY024567)
- Greg D Field
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experimental procedures were reviewed and approved by the Institutional Animal Care and Use Committee of Duke University (protocol A005-16-01).
Reviewing Editor
- Jeremy Nathans, Johns Hopkins University School of Medicine, United States
Version history
- Received: December 11, 2017
- Accepted: March 29, 2018
- Accepted Manuscript published: April 3, 2018 (version 1)
- Version of Record published: May 2, 2018 (version 2)
Copyright
© 2018, Ray et al.
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.
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Further reading
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In the fruit fly Drosophila melanogaster, gustatory sensory neurons express taste receptors that are tuned to distinct groups of chemicals, thereby activating neural ensembles that elicit either feeding or avoidance behavior. Members of a family of ligand -gated receptor channels, the Gustatory receptors (Grs), play a central role in these behaviors. In general, closely related, evolutionarily conserved Gr proteins are co-expressed in the same type of taste neurons, tuned to chemically related compounds, and therefore triggering the same behavioral response. Here, we report that members of the Gr28 subfamily are expressed in largely non-overlapping sets of taste neurons in Drosophila larvae, detect chemicals of different valence, and trigger opposing feeding behaviors. We determined the intrinsic properties of Gr28 neurons by expressing the mammalian Vanilloid Receptor 1 (VR1), which is activated by capsaicin, a chemical to which wild-type Drosophila larvae do not respond. When VR1 is expressed in Gr28a neurons, larvae become attracted to capsaicin, consistent with reports showing that Gr28a itself encodes a receptor for nutritious RNA. In contrast, expression of VR1 in two pairs of Gr28b.c neurons triggers avoidance to capsaicin. Moreover, neuronal inactivation experiments show that the Gr28b.c neurons are necessary for avoidance of several bitter compounds. Lastly, behavioral experiments of Gr28 deficient larvae and live Ca2+ imaging studies of Gr28b.c neurons revealed that denatonium benzoate, a synthetic bitter compound that shares structural similarities with natural bitter chemicals, is a ligand for a receptor complex containing a Gr28b.c or Gr28b.a subunit. Thus, the Gr28 proteins, which have been evolutionarily conserved over 260 million years in insects, represent the first taste receptor subfamily in which specific members mediate behavior with opposite valence.