# Serotonin signaling in control of the Lower Urinary Tract

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $382,499

## Abstract

PROJECT SUMMARY
Normal function of the lower urinary tract (LUT) requires coordination of neuronal activity to allow bladder
filling for urine storage followed later by bladder contraction to accomplish urine expulsion at an appropriate
time and place. Deficiencies in the development of the neural elements that mediate bladder control can
lead to problems in patients such as neurogenic bladder, incontinence, urinary retention, or bladder pain.
These LUT diseases result in reduced quality of life for patients, increase healthcare costs, and burden the
health care system. While we know that the sacral elements of the peripheral nervous system, which
participate in regulation of these bladder processes, include dorsal root ganglion (DRG) sensory neurons
and autonomic (motor) pelvic neurons, there are many gaps in our knowledge regarding how these neurons
develop and how deficits during development lead to congenital defects in bladder control. By surveying
gene expression during development of pelvic ganglia in mice we have identified up-regulation of serotonin
receptors that are also expressed in sensory neurons of developing DRG. Mice with loss of function
mutations in these serotonin receptors, specifically the serotonin type 3 receptor (5-HT3), have abnormal
development of nerves in the bladder wall and later exhibit urinary retention. Our preliminary work in
isolated cultures of sacral neural crest stem cells indicates that perturbations of 5-HT3 signaling disrupt
neuronal differentiation. We postulate that the bladder deficiencies observed in 5-HT3 mutant mice occur
not only as the result of hyper-arborization of developing nerve terminals that lack 5-HT3 signaling, but also
as a consequence of altered cell fate specification leading to imbalances among types of developing DRG
and pelvic ganglia neurons. Cell fate specification is a novel function that has not previously been ascribed
to 5-HT3 and has potential for pronounced impact on the types of neurons formed during development of
bladder innervation. Such alterations in neuronal differentiation would predispose to deficiencies in bladder
control and add to the potential for increased susceptibility to bladder pain. Three aims are proposed that
will elaborate roles for 5-HT3 signaling during development of DRG and pelvic ganglia neurons that
innervate the bladder. In Aim 1 we will use genetic and pharmacologic approaches to determine when 5-
HT3 signaling is required to develop and maintain normal bladder innervation. In Aim 2 we will use
Cre:LoxP lineage tracing studies in Htr3a gain and loss of function mutants to define the developmental
processes and time periods that are affected by 5-HT3 signaling. In Aim 3 we will determine whether
disruptions of 5-HT3 signaling during development increase vulnerabilty to bladder inflammatory pain.
These studies will generate mechanistic knowledge of deficits in neural development that lead to bladder
disease and will aid urologists in sculpting per...

## Key facts

- **NIH application ID:** 9857017
- **Project number:** 5R01DK120025-02
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** E Michelle SOUTHARD-SMITH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $382,499
- **Award type:** 5
- **Project period:** 2019-02-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9857017

## Citation

> US National Institutes of Health, RePORTER application 9857017, Serotonin signaling in control of the Lower Urinary Tract (5R01DK120025-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9857017. Licensed CC0.

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