Brg1 plays an essential role in development and homeostasis of the duodenum through regulation of Notch signaling

Abstract

Brg1, a core subunit of 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 intestinal Brg1 deletion in mice 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, Notch1 intercellular domain (Notch1 ICD) overexpression 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, differentiation, stem cell, and cell survival, of the duodenum. Mechanistically, the rescue of the intestinal Brg1-mutant phenotype by Notch1 ICD overexpression indicates that Notch signaling is a key downstream target that mediates the effects of Brg1.