Cdk5rap3 is essential for intestinal Paneth cell development and maintenance

Michaela Quintero,Richard Blumberg,Yanhua Xia,Yonghong Huang,Ling Hu,Yafei Cai,Yi Zou,Ge Li,Siyang Liu,Nagendra Singh,Hong Xu,Honglin Li

doi:10.1038/s41419-021-03401-8

Abstract

Intestinal Paneth cells are professional exocrine cells that play crucial roles in maintenance of homeostatic microbiome, modulation of mucosal immunity, and support for stem cell self-renewal. Dysfunction of these cells may lead to the pathogenesis of human diseases such as inflammatory bowel disease (IBD). Cdk5 activator binding protein Cdk5rap3 (also known as C53 and LZAP) was originally identified as a binding protein of Cdk5 activator p35. Although previous studies have indicated its involvement in a wide range of signaling pathways, the physiological function of Cdk5rap3 remains largely undefined. In this study, we found that Cdk5rap3 deficiency resulted in very early embryonic lethality, indicating its indispensable role in embryogenesis. To further investigate its function in the adult tissues and organs, we generated intestinal epithelial cell (IEC)-specific knockout mouse model to examine its role in intestinal development and tissue homeostasis. IEC-specific deletion of Cdk5rap3 led to nearly complete loss of Paneth cells and increased susceptibility to experimentally induced colitis. Interestingly, Cdk5rap3 deficiency resulted in downregulation of key transcription factors Gfi1 and Sox9, indicating its crucial role in Paneth cell fate specification. Furthermore, Cdk5rap3 is highly expressed in mature Paneth cells. Paneth cell-specific knockout of Cdk5rap3 caused partial loss of Paneth cells, while inducible acute deletion of Cdk5rap3 resulted in disassembly of the rough endoplasmic reticulum (RER) and abnormal zymogen granules in the mature Paneth cells, as well as loss of Paneth cells. Together, our results provide definitive evidence for the essential role of Cdk5rap3 in Paneth cell development and maintenance.

Highlights

The intestinal epithelium consists of a single layer of epithelial cells, and its primary function includes absorbing nutrients and serving as a barrier against luminal pathogens
Our results clearly demonstrate that Cdk5rap[3] is required in Paneth cell development and maintenance
We examined whether Cdk5rap[3] is involved in stem cell differentiation and Paneth cell specification

Summary

Introduction

The intestinal epithelium consists of a single layer of epithelial cells, and its primary function includes absorbing nutrients and serving as a barrier against luminal pathogens. Cdk[5] activator binding protein Cdk5rap[3] ( known as C53 and LZAP) was originally identified as a binding protein of Cdk[5] activator p35, CBP, and ARF protein[10,11,12] It is highly conserved in multi-cellular organisms, and its orthologues are found in vertebrate, invertebrate and plants but not in yeast and bacteria. Hepatocyte-specific Cdk5rap[3] knockout mice suffered post-weaning lethality, owing to serious hypoglycemia and impaired lipid metabolism[22]. These findings have demonstrated an essential role of Cdk5rap[3] in both embryogenesis and organ development

Methods

Results

Conclusion