5-HT3 Signaling Alters Development of Sacral Neural Crest Derivatives That Innervate the Lower Urinary Tract.

K Elaine Ritter,Yan Guo,E Michelle Southard-Smith,Shilin Zhao,Stephanie B Asher,Karen K Deal,Dennis P Buehler

doi:10.3390/ijms22136838

K Elaine Ritter, Yan Guo + Show 5 more

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https://doi.org/10.3390/ijms22136838

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Abstract

The autonomic nervous system derives from the neural crest (NC) and supplies motor innervation to the smooth muscle of visceral organs, including the lower urinary tract (LUT). During fetal development, sacral NC cells colonize the urogenital sinus to form pelvic ganglia (PG) flanking the bladder neck. The coordinated activity of PG neurons is required for normal urination; however, little is known about the development of PG neuronal diversity. To discover candidate genes involved in PG neurogenesis, the transcriptome profiling of sacral NC and developing PG was performed, and we identified the enrichment of the type 3 serotonin receptor (5-HT3, encoded by Htr3a and Htr3b). We determined that Htr3a is one of the first serotonin receptor genes that is up-regulated in sacral NC progenitors and is maintained in differentiating PG neurons. In vitro cultures showed that the disruption of 5-HT3 signaling alters the differentiation outcomes of sacral NC cells, while the stimulation of 5-HT3 in explanted fetal pelvic ganglia severely diminished neurite arbor outgrowth. Overall, this study provides a valuable resource for the analysis of signaling pathways in PG development, identifies 5-HT3 as a novel regulator of NC lineage diversification and neuronal maturation in the peripheral nervous system, and indicates that the perturbation of 5-HT3 signaling in gestation has the potential to alter bladder function later in life.

Highlights

Dysfunction of the urinary bladder can present as urinary incontinence, neurogenic bladder, or urinary retention
Did the robust and highly specific expression of the Sox10-H2BVenus transgene visualize sacral neural crest (NC) progenitors in situ, it enabled the isolation of NCPs from fetal lower urinary tract (LUT) via fluorescence-activated cell sorting (FACS, Figure 1D) for analysis of transcriptional profiles
Surprisingly little has been discovered about signaling factors that function during development to govern pelvic ganglia neurogenesis and neuronal maturation

Summary

Introduction

Dysfunction of the urinary bladder can present as urinary incontinence, neurogenic bladder, or urinary retention. These disorders afflict millions of people worldwide and dramatically impact quality of life [1,2]. Bladder dysfunction is caused by damage to the nerves that supply the LUT. The cell bodies of the autonomic neurons that innervate the bladder are situated some distance away from the bladder itself, unlike many other autonomic neurons that are in close proximity to their target organs. There is growing interest in understanding the developmental processes that govern the formation and maturation of LUT innervation as a means to devise novel strategies to restore bladder function [4]

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