# Mechanistic studies of molecular recognition and signaling of neuronal wiring receptors

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2024 · $490,273

## Abstract

Project Abstract:
Circuit assembly, the collection of sequential developmental steps that ultimately lead to the formation of
synapses, is a conserved process that determines organismal function and behavior. In humans, billions of
neurons make trillions of synapses, and proper circuit function depends on correct synaptic partnerships.
Perturbations in circuit assembly can lead to devastating neurodevelopmental diseases. While it is generally
accepted that synaptic connectivity is determined by cell surface receptor interactions, only a relatively small
number of these receptors have been identified, and the developmental signaling pathways downstream of these
molecules remain mostly uncharacterized. Given the complexity of nervous systems, we need to expedite the
discovery of neural receptor/ligand pairs and learn how they signal in order to understand brain development
and the physiology of diseases where neural wiring is fundamental. Our labs leverage biochemical and genetic
insights into cell surface protein interactions to identify new connectivity codes and corresponding signaling
pathways. Previously, in an unbiased protein interaction biochemical screen, we identified two Drosophila
interaction networks within the immunoglobulin superfamily – Dprs/DIPs and Beats/Sides. These “interaction
codes” guide cell-cell interactions that underlie circuit assembly. Most members of these families bind each other
in a complex yet specific manner; for example, each Dpr can interact with a specific subset of DIPs and vice
versa. The expression patterns of these proteins are stereotyped, and combinatorial expression of Dprs, DIPs,
Beats and/or Sides has been observed, likely serving as unique identity markers on cell surfaces. Deletion of
these proteins lead to neural connectivity phenotypes, and specifically for Dpr11 and DIP-γ, misregulation of
BMP signaling and neuronal death. Here, we propose to uncover the molecular pathways that are downstream
of Dpr-DIP interactions and discover and study other cell surface receptors and secreted proteins that mediate
Dpr/DIP function via direct interactions. Our exciting preliminary results already revealed new co-receptors, and
follow-up experiments will include biophysical and structural characterization of these new interactions, followed
by signaling assays in culture and genetic perturbations in vivo to establish functional roles for these interactions.
Furthermore, we will reveal the structural basis of Beat-Side interactions, examine their complexes, manipulate
the hetero and homodimeric binding abilities of these proteins and test them using established phenotypes in
the embryonic and larval neuromuscular system.

## Key facts

- **NIH application ID:** 10973119
- **Project number:** 1R01NS139060-01
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Robert Arnulfo Carrillo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $490,273
- **Award type:** 1
- **Project period:** 2024-06-04 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10973119

## Citation

> US National Institutes of Health, RePORTER application 10973119, Mechanistic studies of molecular recognition and signaling of neuronal wiring receptors (1R01NS139060-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10973119. Licensed CC0.

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