# Circuit-specific transcriptional mechanisms underlying the precision of synaptic connectivity

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2020 · $365,969

## Abstract

The precise assembly of neural circuits provides the basis for nervous system function and animal behavior.
Laminar arrangement of neural connections is a primary strategy for organizing neural circuits in vertebrates
and invertebrates. Previous research has illuminated how particular neuron types target to and arborize within
specific layers in isolated contexts. However, how the targeting and morphogenesis of different neuron types is
coordinated to establish layered networks of connections is unknown. Addressing this gap in knowledge is
fundamentally important to understanding how neural circuits are established. The goal of our research is to
identify general molecular and cellular principles underlying the construction of layered neural networks. To
accomplish this, our strategy is to determine how cells are coordinated to specific layers, and identify
commonalities in how different layers assemble to illuminate general mechanisms. This approach requires
precise knowledge of the cell types that innervate specific layers and genetic access to these cell types during
development. Therefore, we study layer assembly in the Drosophila visual system, wherein well-characterized
genetically accessible cell types synapse within specific layers in a stereotyped manner. In the Drosophila
medulla, more than 60 uniquely identifiable neuron types synapse within 10 parallel layers. Previous studies
indicate that medulla layers are refined during development from broad domains through a precise sequence
of interactions between specific cell types. Similar findings in the mouse retina suggests this is a conserved
developmental strategy for building synaptic layers. The main thrust of the proposal is to determine the
molecular logic governing broad domain organization and the refinement of layers from these regions. We
recently showed that Drosophila Fezf (dFezf), a conserved transcription factor, controls the assembly of a
specific layer by coordinating the layer-specific innervation of different cell types. Based on preliminary
findings, we hypothesize that (1) dFezf acts through a network of transcriptional regulators to control a gene
program that regulates early and late stages of layer refinement, and (2) the use of transcriptional modules
(like dFezf) to coordinate layer-specific innervation represents a general mechanism for constructing discrete
layers. We will test this in 3 Specific AIMs. In AIMs I and II, we use dFezf as a handle to address the molecular
underpinnings of (I) broad domain organization within the early medulla, and (II) the stepwise refinement of a
specific layer. In AIM III we determine if transcriptional modules analogous to dFezf function generally to
orchestrate the assembly of medulla layers. As the Drosophila visual system is analogous to the vertebrate
retina in structure and function, and research in the mouse cortex is consistent with Fezf2 regulating the
assembly of laminar circuitry, we expect our findings will have broad...

## Key facts

- **NIH application ID:** 9875490
- **Project number:** 5R01NS103905-02
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** David D GINTY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $365,969
- **Award type:** 5
- **Project period:** 2019-03-01 → 2021-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9875490

## Citation

> US National Institutes of Health, RePORTER application 9875490, Circuit-specific transcriptional mechanisms underlying the precision of synaptic connectivity (5R01NS103905-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9875490. Licensed CC0.

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