# A novel mechanism for synapse localization in the retina

> **NIH NIH R21** · HARVARD MEDICAL SCHOOL · 2022 · $204,913

## Abstract

PROJECT SUMMARY
Neural circuit function depends on the precise organization of diverse types of synapses. In the vertebrate retina,
key computations are performed by parallel networks of microcircuits that form highly ordered systems of
synapses that are confined to discrete regions of neuropil. For instance, retinal amacrine cells integrate and
compute inputs and then communicate this information to retinal ganglion cells via synapses in the inner
plexiform layer (IPL). Although we have begun to identify the molecular mechanisms that dictate what type of
synapse should form, we still know very little about how synaptic location is controlled. Our long term goal is to
define a molecular pathway for synapse localization. The specific objective of this exploratory project is to test
the new hypothesis that the atypical cadherin Fat3 determines where synapses will form by harnessing the
activity of two known synaptogenic molecules, the WAVE Regulatory Complex (WRC) and the receptor tyrosine
phosphatase protein PTPdelta. Data generated during the course of this work will allow us to update our model and
develop a more focused investigation of this pathway in the future.
Several observations suggest that Fat3 interacts with the WRC and PTP? to control synapse localization in the
retina. Fat3 belongs to a family of atypical cadherins with known roles in planar polarity, a signaling system that
creates and aligns asymmetries in neighboring cells by creating molecular subdomains (5). The Fat3 intracellular
domain harbors multiple binding sites for diverse effectors, including known cytoskeletal regulators and synaptic
components, such as the WRC and PTPdelta. Thus, Fat3 is well-suited to respond to signals in neighboring cells
and then induce appropriate intracellular responses needed for synapse development. Consistent with this idea,
in fat3 mutant mice, retinal amacrine cells show altered patterns of migration and retain extra processes outside
of the IPL that go on to form an ectopic plexiform layer (4). Further, by creating and analyzing mice harboring
deletions of various regions of the Fat3-ICD, we found that Fat3’s effects on migration and neurite retraction can
be separated from its effects on synapse development. Importantly, Fat3-dependent synapse development
appears to depend specifically on interactions with the WRC and PTPdelta. The WRC is a well-studied regulator of
local changes to the actin cytoskeleton, including at the synapse (12), while PTPdelta is known to be important for
synapse development elsewhere in the nervous system (13-15). To follow up on these observations, we will use
a combination of biochemical and genetic approaches to characterize physical interactions among Fat3, WRC,
and PTP?; test whether retinal synapse development in wild-type and fat3 mutant mice requires WRC function;
and determine how Fat3 and PTPdelta influence each other’s distribution and function by examining single and
double mutant mouse strains.

## Key facts

- **NIH application ID:** 10308520
- **Project number:** 5R21EY032392-02
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Lisa Goodrich
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $204,913
- **Award type:** 5
- **Project period:** 2020-12-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10308520

## Citation

> US National Institutes of Health, RePORTER application 10308520, A novel mechanism for synapse localization in the retina (5R21EY032392-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10308520. Licensed CC0.

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