한빛사논문
- 조회582
Jong Hoon Won1, Jacob S. Choi1,2 & Joon-Il Jun1,*
1Department of Biochemistry and Molecular Genetics, College of Medicine, The University of Illinois at Chicago, 900 South Ashland Avenue, Chicago, IL 60607, USA. 2Present address: Department of Medicine, Northwestern University, 676 North St. Clair street Arkes Suite 2330, Chicago, IL 60611, USA
*Corresponding author.
Abstract
Intestinal stem cells (ISCs) at the crypt base contribute to intestinal homeostasis through a balance between self-renewal and differentiation. However, the molecular mechanisms regulating this homeostatic balance remain elusive. Here we show that the matricellular protein CCN1/CYR61 coordinately regulates ISC proliferation and differentiation through distinct pathways emanating from CCN1 interaction with integrins αvβ3/αvβ5. Mice that delete Ccn1 in Lgr5 + ISCs or express mutant CCN1 unable to bind integrins αvβ3/αvβ5 exhibited exuberant ISC expansion and enhanced differentiation into secretory cells at the expense of absorptive enterocytes in the small intestine, leading to nutrient malabsorption. Analysis of crypt organoids revealed that through integrins αvβ3/αvβ5, CCN1 induces NF-κB-dependent Jag1 expression to regulate Notch activation for differentiation and promotes Src-mediated YAP activation and Dkk1 expression to control Wnt signaling for proliferation. Moreover, CCN1 and YAP amplify the activities of each other in a regulatory loop. These findings establish CCN1 as a niche factor in the intestinal crypts, providing insights into how matrix signaling exerts overarching control of ISC homeostasis.
논문정보
- Research article
- 2022년 06월 (BRIC 등록일 2022-06-08)
- 국외 연구진
- 생명과학 > 분자생물학
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