Glycogen Synthase Kinase 3 Is Essential for Intestinal Cell Niche and Digestive Function

TL;DR

This study shows that GSK3 is crucial for maintaining intestinal structure and function, and its absence leads to severe digestive issues and stem cell abnormalities.

Contribution

The study reveals the essential role of GSK3 in intestinal niche maintenance and digestive function, distinct from APC mutation effects.

Findings

Complete GSK3 deletion in mice causes perinatal lethality and intestinal architecture disruption.

GSK3 deficiency leads to stem cell and Paneth cell mislocalization and impaired nutrient absorption.

Deleting β-catenin in GSK3-deficient mice partially restores intestinal function and niche integrity.

Abstract

Glycogen synthase kinase 3 (GSK3) contains two isoforms, GSK3α and GSK3β, which are key negative regulators of the Wnt/β-catenin signaling pathway. This study focuses on investigating the role of GSK3 in intestinal function. We found that GSK3α and GSK3β exhibit functional redundancy in the intestine. However, complete loss of GSK3 resulted in lethality in mice, accompanied by disruption of the intestinal cellular niche, aberrant proliferation and mislocalization of stem cells and Paneth cells, as well as impaired intestinal absorption and motility. Despite that both GSK3 deficiency and APC mutation led to upregulated β-catenin expression, the intestinal phenotypes of GSK3-deficient mice were different from ApcMin/+ mice. Notably, deletion of β-catenin partially rescued the hyperproliferation and mislocalization of Paneth cells and contributed to the restoration of the intestinal niche and function. Our findings indicate the essential role of GSK3 in maintaining intestinal homeostasis and reveal the dual function of the GSK3/β-catenin axis in regulating intestinal stem cell development and absorptive function.

WNT/β-catenin signaling is essential for intestinal stem cell development and self-renewal, while its dysregulation can drive tumorigenesis. GSK3, a key negative regulator of β-catenin, in intestinal homeostasis remains incompletely understood. In this study, we investigated the role of GSK3 in intestinal development, niche maintenance, and physiological function. Unlike ApcMin/+ mice that developed intestinal polyps, neither GSK3α nor GSK3β deficiency disrupted intestinal homeostasis. However, complete GSK3 deletion (DKO) resulted in perinatal lethality, characterized by disturbed crypt–villus architecture, Paneth cell redistribution, and villus elongation. GSK3 deficiency disrupted the intestinal niche, leading to expanded and mislocalized stem cells and Paneth cells, along with reduced tuft and enteroendocrine cells. These alterations impaired nutrient absorption and gut motility. Mechanistically, β-catenin-positive cells were significantly increased following GSK3 deletion. Genetic ablation of β-catenin under GSK3-deficient conditions reduced stem and Paneth cell populations while restoring tuft and enteroendocrine cells, thereby ameliorating niche abnormalities and improving absorptive and peristaltic functions. This study indicates the essential role of GSK3/β-catenin signaling in maintaining intestinal niche integrity and digestive physiology, highlighting potential therapeutic targets for intestinal and digestive disorders.

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