# MICROENVIRONMENT IN ENTERIC NEURON DEVELOPMENT

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $438,742

## Abstract

The enteric nervous system (ENS) is the largest and most complex division of the peripheral nervous system.
The ENS is uniquely able to function without input from the CNS. We have demonstrated that enteric neurons
are born (undergo terminal mitosis) in a reproducible order in which early-born mature neurons coexist with
and innervate still-dividing precursors. Serotonergic and cholinergic neurons are born first, while neurons that
contain tyrosine hydroxylase (TH), g-aminobutyric acid (GABA), or calcitonin gene related peptide (CGRP) are
born later. This observation led us to frame the hypothesis that the activity of early-born neurons can, through
their neurotransmitters, 5-HT and/or acetylcholine (ACh), affect the development of later-born neurons.
Supporting of this idea, we showed that 5-HT, through 5-HT4 receptors, promotes development of TH-, GABA-,
and CGRP-containing neurons, that these phenotypes are deficient, and the ENS is hypoplastic when
tryptophan hydroxylase 2 (TPH2) is deleted and mice thus lack neuronal 5-HT. The late-born neurons are also
deficient and the ENS is hypoplastic in animals that carry an autism-associated human variant of the serotonin
transporter (SERT; SERT Ala56 or G56A), which is hyperfunctional and clears 5-HT from its receptors too
rapidly. In contrast, mice that lack SERT (SERTKO) or which are exposed during development to a SERT
inhibitor have a hyperplastic ENS and excessive numbers of late-born neurons. Recent preliminary data,
obtained with mice that under- or overexpress the presynaptic choline transporter, suggest that ACh functions
like 5-HT. Because serotonergic and cholinergic neurons are thus essential for ENS development, defects in
their signaling during ontogeny lead, not only to ENS hypo-or hyperplasia, but to dysmotilities and abnormally
regulated mucosal growth that are readily demonstrated in adult animals. We thus postulate that the defects
that arise due to errant serotonergic or cholinergic signaling in ontogeny, possibly due to environmental
perturbations, contribute to dysmotility disorders in adults. Although TPH2-derived 5-HT is more important than
that from TPH1 in ENS formation under basal conditions, TPH1-derived 5-HT from “pre-enteric” sources,
(placenta, yolk sac, and maternal circulation) may be essential to support ENS neurogenesis prior to
development of serotonergic neurons. TPH1-derived 5-HT from mucosal enterochromaffin (EC) cells may also
disturb ENS neurogenesis and/or function if it reaches the neuronal compartment. We now plan to test 3
overarching hypotheses: (i) “Pre-enteric” TPH1-derived 5-HT is essential to support enteric neurogenesis
before serotonergic neurons develop. (ii) Mucosal SERT activity is essential to prevent 5-HT from overflowing
from the mucosa to disturb neurogenesis and/or neuronal function; insults that up- or downregulate SERT thus
cause abnormal ENS formation and adult function. (iii) Early-born enteric cholinergic neurons act on
muscarinic recep...

## Key facts

- **NIH application ID:** 10328928
- **Project number:** 5R01NS015547-39
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** MICHAEL D GERSHON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $438,742
- **Award type:** 5
- **Project period:** 1979-12-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10328928

## Citation

> US National Institutes of Health, RePORTER application 10328928, MICROENVIRONMENT IN ENTERIC NEURON DEVELOPMENT (5R01NS015547-39). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10328928. Licensed CC0.

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