# Development and Disease of the Human Proximal Enteric Nervous System

> **NIH NIH F31** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $38,201

## Abstract

Project Summary/Abstract
The enteric nervous system (ENS) is a complex network of peripheral neurons and glial cells that controls gut
motility by coordinating the involuntary contraction and relaxation of innervated smooth muscle along the
length of the gastrointestinal tract. While the ENS of the intestine is particularly well-studied, the development,
function, and disease pathologies of more proximal ENS are largely unstudied. The preganglionic control of the
esophagus has been studied at the level of the CNS and the vagus nerve that controls distal GI motility, but the
peripheral neuroglial network that is embedded within the foregut, the relative distribution neuronal subtypes
and glia, and the basic architecture of how the ENS interfaces with the postsynaptic tissues in the esophagus
and stomach are largely undetermined. Moreover, the basic process by which the enteric neuroglial network of
the proximal ENS is assembled during embryonic development is virtually unstudied. Understanding how
neurons connect with its target cell types will provide critical insight into how the proximal ENS functions
postnatally. Additionally, developmental studies were foundational for recent successes in engineering human
small intestinal tissues with a functional ENS. While these types of approaches to study innervation of the
foregut have not been done, they are critical if we are to understand peripheral control of foregut tissue
function. In this proposal, we aim to 1) map the molecular and cellular architecture of the proximal ENS, 2)
identify mesenchymal signals that control proximal ENS development, and 3) generate human foregut tissues
with a functional ENS. We have identified that mouse embryos lacking the transcription factor Osr1 lack an
ENS in the proximal gut. While esophageal and gastric epithelium and mesenchyme are present in these e13.5
Osr-/- embryos, enteric neurons and smooth muscle are virtually absent. In our first aim, we will identify the
primary developmental defects of proximal ENS development in Osr1 mutant embryos. Based on our
transcriptional analysis of foregut tissue isolated from e9.5 Osr-/- embryos, we hypothesize that Osr1 functions
predominantly in the mesenchyme to control ENS development. We will use a mouse genetic approach to
delete Osr1 specifically in mesenchyme, as well as in ENCCs and endoderm, to identify germ-layer specific
roles of Osr1 in proximal ENS development. We have also identified several signaling pathways, which are
known to regulate ENS formation, that are perturbed in e9.5 Osr-/- embryos, including RA, Semaphorin, and
BMP. We hypothesize that Osr1 mutant mesenchyme has disrupted expression of key signaling molecules that
act in a paracrine fashion to control proximal ENS development. In our second aim, we will use a highly
manipulable in vitro culture system, to examine the effects of Osr1-regulated signaling pathways on proximal
ENS development. We will generate human esophageal organoids with a func...

## Key facts

- **NIH application ID:** 9938569
- **Project number:** 5F31DK118823-03
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Alexandra Eicher
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $38,201
- **Award type:** 5
- **Project period:** 2018-07-16 → 2021-07-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9938569

## Citation

> US National Institutes of Health, RePORTER application 9938569, Development and Disease of the Human Proximal Enteric Nervous System (5F31DK118823-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9938569. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*