# Reverse-engineering mechanisms of neural circuit wiring in the fly visual system

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $313,685

## Abstract

Project Summary
 A central question in neuroscience is how neural circuits self-organize during development into functional
structures. Neural circuit function relies on the precise specification of synapses, while alterations of synaptic
connectivity are associated with numerous neurodevelopmental disorders. Seminal studies have identified
mutations and molecular mechanisms that alter brain wiring. Yet, how this genetic information ultimately leads
to self-assembly of neural circuits is poorly understood. What developmental programs lead to functional
neuronal structures? What rules describe these programs? How do cells implement these rules?
 The Drosophila visual system represents a remarkable instance of the circuit self-assembly problem in the
developing brain. The compound eye (consisting of ~800 ommatidia) is wired through a principle of “neural
superposition” (NSP): 800 times six photoreceptors that see the same point in space, yet originate from six
different ommatidia, find each other in the lamina and ‘wire together’ in synaptic cartridges. The correct sorting
of photoreceptor growth cones results in a six-fold increase in light-gathering sensitivity without loss of spatial
resolution. However, it is poorly understood how 4800 elongating growth cones stop at target cartridges with
an astonishing accuracy of greater than 99%.
 In preliminary studies, we established the ability to use non-invasive, live-imaging based on multi-photon
microscopy of intact and normally developing pupae to assay photoreceptor growth cone dynamics during
NSP. Using this approach, we obtained the first quantitative measurements of individual growth cone dynamics
throughout the entire NSP process and established that the complex program of NSP could arise from three
simple local rules, which govern how growth cones anchor, elongate and stop in the lamina. Our work
suggested the hypothesis that a cellular decision to stop wiring could arise from collective interactions with
neighboring cells, and that these interactions could buffer biological variation, such as imperfect direction of
growth cone elongation. To investigate collective stop decisions during NSP, we will: (Aim 1) experimentally
determine potential times and places where growth cone fronts, backs and target cells could physically
interact; (Aim 2) use these data to constrain computational models that systematically compare different
models of stop rules; and (Aim 3) experimentally search for signatures of error propagation of NSP wiring in
mutant conditions and identify molecular components that participate in the implementing the stop rule.
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## Key facts

- **NIH application ID:** 9967065
- **Project number:** 5R01EY028205-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** STEVEN J ALTSCHULER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $313,685
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9967065

## Citation

> US National Institutes of Health, RePORTER application 9967065, Reverse-engineering mechanisms of neural circuit wiring in the fly visual system (5R01EY028205-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9967065. Licensed CC0.

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