BMP suppresses Wnt signaling via the Bcl11b-regulated NuRD complex to maintain intestinal stem cells

EMBO J. 2024 Dec;43(23):6032-6051. doi: 10.1038/s44318-024-00276-1. Epub 2024 Oct 21.

Abstract

Lgr5+ intestinal stem cells (ISCs) are crucial for the intestinal epithelium renewal and regeneration after injury. However, the mechanism underlying the interplay between Wnt and BMP signaling in this process is not fully understood. Here we report that Bcl11b, which is downregulated by BMP signaling, enhances Wnt signaling to maintain Lgr5+ ISCs and thus promotes the regeneration of the intestinal epithelium upon injury. Loss of Bcl11b function leads to a significant decrease of Lgr5+ ISCs in both intestinal crypts and cultured organoids. Mechanistically, BMP suppresses the expression of Bcl11b, which can positively regulate Wnt target genes by inhibiting the function of the Nucleosome Remodeling and Deacetylase (NuRD) complex and facilitating the β-catenin-TCF4 interaction. Bcl11b can also promote intestinal epithelium repair after injuries elicited by both irradiation and DSS-induced inflammation. Furthermore, Bcl11b deletion prevents proliferation and tumorigenesis of colorectal cancer cells. Together, our findings suggest that BMP suppresses Wnt signaling via Bcl11b regulation, thus balancing homeostasis and regeneration in the intestinal epithelium.

Keywords: BMP Signaling; Bcl11b; Colorectal Cancer; Intestinal Stem Cells; Wnt Signaling.

MeSH terms

  • Animals
  • Bone Morphogenetic Proteins* / genetics
  • Bone Morphogenetic Proteins* / metabolism
  • Cell Proliferation
  • Humans
  • Intestinal Mucosa* / metabolism
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex* / genetics
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Repressor Proteins* / genetics
  • Repressor Proteins* / metabolism
  • Stem Cells* / metabolism
  • Tumor Suppressor Proteins
  • Wnt Signaling Pathway*
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • Repressor Proteins
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex
  • Bone Morphogenetic Proteins
  • Lgr5 protein, mouse
  • Receptors, G-Protein-Coupled
  • BCL11B protein, human
  • beta Catenin
  • Tumor Suppressor Proteins