Interindividual Variation in Gut Nitrergic Neuron Density Is Regulated By GDNF Levels and ETV1.

Area of Science:

• Neuroscience
• Gastroenterology
• Genetics

Background:

• The enteric nervous system (ENS) shows significant individual variation in size and function.
• ENS dysfunction is implicated in numerous common human diseases.
• Understanding the regulation of ENS variation is crucial for disease etiology.

Purpose of the Study:

• To investigate the mechanisms regulating interindividual variation in ENS size and function.
• To identify key molecular players influencing ENS development and gut physiology.
• To establish a link between GDNF levels and ENS-mediated gut function.

Main Methods:

• Analysis of RNA sequencing data from human colon biopsies and developing gut.
• Utilized mouse models with specific alleles to alter candidate effector molecule levels.
• Employed siRNA, primary neuronal cultures, and functional gut assays in mice.

Main Results:

• Human colon GDNF levels exhibit a 5-fold variation, correlating with nitrergic marker expression.
• GDNF regulation in the gut involves its 3' untranslated region (3' UTR), with conserved roles for miR-9 and miR-133.
• Increased inhibitory nitrergic innervation, driven by GDNF, leads to slower gut transit, larger stool size, and altered water content.

Conclusions:

• Normal variation in GDNF levels significantly influences ENS size, composition, and gut function.
• GDNF regulates nitrergic lineage development through ETV1 induction.
• These findings provide a mechanistic explanation for observed interindividual variations in ENS parameters and gut function.