Brg1, a core subunit of the SWI/SNF chromatin remodeling complex, is essential for development and homeostasis of various organs. However, the functional role of Brg1 in intestinal development and homeostasis, and the underlying molecular mechanism, remain unknown. We found that deletion of Brg1 in the mouse intestine resulted in growth impairment and early death associated with abnormal crypt-villous formation, skewed differentiation into secretory lineage cells, markedly increased apoptosis, and stem cell loss in the duodenum. Furthermore, we found that the Notch signaling pathway was dramatically downregulated in Brg1-deficient duodenum. Remarkably, overexpression of the Notch1 intercellular domain (ICD) partially reversed the prognosis of intestinal Brg1 mutant mice. Notch1 ICD overexpression rescued morphogenesis, prevented over-differentiation into secretory lineage cells, and restored apoptosis to normal levels in Brg1-deficient duodenum, although stem cell loss was not rescued. Our data demonstrate that Brg1 plays an essential role in development and homeostasis, including morphogenesis, stem cell differentiation and cell survival in the duodenum. Mechanistically, the rescue of the intestinal Brg1 mutant phenotype by overexpression of the Notch1 ICD indicates that Notch signaling is a key downstream target that mediates the effects of Brg1.
Author contributions
Y.T. and A.F. conceived and designed the study. Y.T. performed the experiments. Y.T., A.F. and H.S. analyzed the data. Y.T., A.F., T.C. and H.S. wrote the manuscript.
Funding
This work was supported by the Japan Society for the Promotion of Science (JSPS) [KAKENHI 25112707, 25130706, 26293173 to H.S.; 25461021 to A.F.]; the Ministry of Education, Culture, Sports, Science, and Technology of Japan [15K15290 Research program of the Project for Development of Innovative Research on Cancer Therapeutics (P-Direct) to H.S.]; the Ministry of Health, Labour and Welfare [Health and Labour Sciences Research Grants for Research on Intractable Diseases, Hepatitis and The innovative development and the practical application of new drugs for hepatitis B to T.C.; Comprehensive Research on Life-Style Related Diseases including Cardiovascular Diseases and Diabetes Mellitus to H.S.; The Development of Innovative Therapeutic Drug for the Intractable Inflammatory Bowel Disease to H.S.]; Kobayashi Foundation for Cancer Research (to H.S.); The Naito Foundation (to H.S.); Princess Takamatsu Cancer Research Foundation [13-24514 to H.S.]; The Mochida Foundation (to A.F.); The Kanae Foundation (to A.F.); The Suzuki Kenzou Foundation (to A.F.); The Takeda Foundation (to A.F.); The Japanese Society of Gastroenterology (to A.F.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
