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Shp2/MAPK signaling controls goblet/paneth cell fate decisions in the intestine

Julian Heuberger1, Frauke Kosel, Jingjing Qi

  • 1Laboratory of Signal Transduction in Development and Cancer and Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.

Proceedings of the National Academy of Sciences of the United States of America
|February 20, 2014
PubMed

Insights

Shp2-mediated MAPK signaling dictates intestinal cell fate, controlling goblet and Paneth cell development. This pathway also influences leucine-rich repeat-containing receptor 5 (Lgr5)+ stem cell niches and Wnt/β-catenin activity.

Area of Science:

  • Developmental biology
  • Cell signaling
  • Gastrointestinal biology

Background:

  • Notch and Wnt/β-catenin signals are crucial for mammalian intestinal development, regulating stem cell maintenance and differentiation.
  • The precise mechanisms governing progenitor differentiation into goblet, Paneth, or enteroendocrine cells remain incompletely understood.

Purpose of the Study:

  • To investigate the role of Shp2-mediated MAPK signaling in regulating intestinal progenitor cell fate decisions.
  • To elucidate the impact of Shp2/MAPK signaling on leucine-rich repeat-containing receptor 5 (Lgr5)+ stem cell populations and their niches.

Main Methods:

  • Conditional mutagenesis in mice to ablate or activate specific signaling pathways (Shp2, Mek1) in the intestinal epithelium.
  • Analysis of cell fate markers and stem cell populations (Lgr5+ cells).
  • Inhibition of MAPK signaling in intestinal organoids and cultured cells to assess effects on Wnt/β-catenin activity and Tcf4 isoforms.

Main Results:

  • Ablation of Shp2 reduced MAPK signaling, decreasing goblet cells and increasing Paneth cells, while expanding Lgr5+ stem cell niches.
  • Conditional activation of Mek1 reversed the Shp2 ablation phenotype, promoting goblet cells and inhibiting Paneth cells, and restricting Lgr5+ stem cell expansion.
  • MAPK pathway inhibition altered Tcf4 isoform abundance, enhancing Wnt/β-catenin activity.

Conclusions:

  • Shp2-mediated MAPK signaling is a key determinant of the goblet versus Paneth cell fate choice.
  • This signaling pathway influences Lgr5+ stem cell populations and their niches, potentially through direct effects or via Paneth cells.
  • Shp2/MAPK signaling regulates Wnt/β-catenin activity, thereby controlling intestinal secretory lineage differentiation.
Keywords:
Mek1DDPTPN11RTKTCF7L2crypt

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