Cdk5rap3 is essential for intestinal Paneth cell development and maintenance.
Cdk5rap3 is essential for intestinal Paneth cell development and maintenance.
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Cdk5rap3 对于肠道潘氏细胞的发育和维持至关重要。
DOI：
10.1038/s41419-021-03401-8
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发表时间：
2021-01-27
影响因子：
9
通讯作者：
Li H
中科院分区：
文献类型：
--
作者：
Quintero M;Liu S;Xia Y;Huang Y;Zou Y;Li G;Hu L;Singh N;Blumberg R;Cai Y;Xu H;Li H
肠潘氏细胞是专职外分泌细胞，在维持体内平衡的微生物组、调节粘膜免疫和支持干细胞自我更新中发挥关键作用。这些细胞的功能障碍可能导致人类疾病的发病机制，如炎症性肠病（IBD）。Cdk5激活剂结合蛋白Cdk5rap3（也称为C53和LZAP）最初被鉴定为Cdk5激活剂p35的结合蛋白。虽然以前的研究表明，它参与了广泛的信号通路，Cdk5rap3的生理功能仍然在很大程度上不确定。在这项研究中，我们发现Cdk5rap3缺陷导致非常早期的胚胎致死，表明其在胚胎发生中不可或缺的作用。为了进一步研究其在成年组织和器官中的功能，我们建立了肠上皮细胞（IEC）特异性敲除小鼠模型，以研究其在肠道发育和组织稳态中的作用。IEC特异性Cdk5rap3缺失导致潘氏细胞几乎完全丧失，并增加了对实验诱导的结肠炎的易感性。有趣的是，Cdk5rap3缺陷导致关键转录因子Gfi1和Sox 9的下调，表明其在潘氏细胞命运规范中的关键作用。此外，Cdk5rap3在成熟潘氏细胞中高度表达。潘氏细胞特异性敲除Cdk5rap3导致潘氏细胞的部分损失，而可诱导的Cdk5rap3的急性缺失导致成熟潘氏细胞中粗面内质网（RER）和异常酶原颗粒的解体，以及潘氏细胞的损失。总之，我们的研究结果提供了明确的证据Cdk5rap3在潘氏细胞的发育和维护中的重要作用。
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.
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