Cdk5rap3 is essential for intestinal Paneth cell development and maintenance
| Autor: | Yi Zou, Ling Hu, Siyang Liu, Michaela Quintero, Nagendra Singh, Yafei Cai, Hong Xu, Yanhua Xia, Honglin Li, Ge Li, Yonghong Huang, Richard S. Blumberg |
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| Rok vydání: | 2021 |
| Předmět: |
Paneth Cells
Cancer Research Ubiquitylation Immunology Cell Cycle Proteins Biology digestive system Article Mice Cellular and Molecular Neuroscience Downregulation and upregulation medicine Animals lcsh:QH573-671 Transcription factor Tissue homeostasis Mice Knockout lcsh:Cytology Tumor Suppressor Proteins Cell Differentiation Cell Biology Zymogen granule Embryonic stem cell Cell biology Mice Inbred C57BL medicine.anatomical_structure Differentiation Paneth cell Knockout mouse Stem cell Signal Transduction |
| Zdroj: | Cell Death & Disease Cell Death and Disease, Vol 12, Iss 1, Pp 1-14 (2021) |
| ISSN: | 2041-4889 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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