# Genetic and extrinsic mechanisms governing early enteric nervous system development

> **NIH NIH R01** · RICE UNIVERSITY · 2024 · $382,143

## Abstract

Resident between the muscle walls of the entire gastrointestinal (GI) tract, the enteric nervous system
(ENS) consists of a series of interconnected neurons and glia, numbered in the hundreds of millions. The
ENS controls essential gut functions, such as peristalsis, water balance and intestinal barrier homeostasis.
The ENS is derived from enteric neural progenitors (ENPs) that migrate into the developing gut tube during
embryogenesis and differentiate into enteric neurons or glia. Disruption in ENS formation results in the
congenital condition Hirschsprung disease (HSCR), in which variable regions of the GI lack ENS—the most
common form of HSCR presents along the distal colon, also known as colonic aganglionosis. The
underlying cellular mechanisms that ENPs utilize to migrate into and spatially position along the gut tube,
as well as genetic programs they execute to differentiate into enteric neurons have not been well studied
in vivo, therefore limiting our knowledge of how the ENS manifests. The overall goal is to expand
foundational knowledge of the genes utilized to execute the complex mechanisms necessary for ENS
formation, with an eye for informing downstream translational therapeutic studies. In this proposal, we
utilize zebrafish embryos due to their genetic conservation with humans, the ease of viewing their external
development and for their optical transparency. Building off of single-cell transcriptomic data sets generated
from ENP cells collected during their early neurogenesis along the gut tube, Aim 1 will examine a
hypothesis that the spatial arrangement of newly uncovered ENP transcriptional subpopulations predict
future enteric neuron placement and terminal differentiation along the gut tube. In agreement with and
extending observations in mammalian models, we have recently discovered that Retinoic Acid (RA)
signaling is critical globally during early steps of zebrafish ENS development; however, how RA signaling
autonomously influences ENS ontogenesis in vivo is not well understood in any system to date. Aim 2 will
investigate a hypothesis that the RA pathway autonomously controls ENP differentiation states and
migration patterns along the gut tube using cutting edge single-cell transcriptomics, optogenetics and in
vivo imaging. We will also test a mechanistic model in Aim 2 that candidate transcription factors function
intrinsically downstream of RA in ENPs to govern ENS formation, thereby expanding our understanding of
the ENS gene regulatory network. Aim 3 will use genetic modulation of the cell cycle, quantitative in vivo
imaging and cell tracking test a cellular mechanistic model that ENPs couple proliferation with migration to
dictate proper enteric neuron patterning in the gut downstream of the RA pathway. The results of these
aims will significantly increase our knowledge of the genetic, molecular and cellular underpinnings of ENP
development and early ENS creation and they will provide a new mechanistic framework for s...

## Key facts

- **NIH application ID:** 10789883
- **Project number:** 5R01DK124804-04
- **Recipient organization:** RICE UNIVERSITY
- **Principal Investigator:** Rosa A Uribe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $382,143
- **Award type:** 5
- **Project period:** 2021-03-27 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10789883

## Citation

> US National Institutes of Health, RePORTER application 10789883, Genetic and extrinsic mechanisms governing early enteric nervous system development (5R01DK124804-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10789883. Licensed CC0.

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