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Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation

A Rangarajan1, C Talora, R Okuyama

  • 1Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.

The EMBO Journal
|July 4, 2001
PubMed

Insights

Notch signaling controls skin cell growth and differentiation. Deleting Notch1 causes skin overgrowth, while activating Notch1 halts growth by increasing p21 expression and promoting early differentiation.

Area of Science:

  • Cell Biology
  • Developmental Biology
  • Dermatology

Background:

  • The precise role of Notch signaling in mammalian epithelial cell growth and differentiation remains unclear.
  • Notch signaling pathways are crucial for cell-cell communication and play significant roles in development and disease.

Purpose of the Study:

  • To elucidate the function of Notch1 in keratinocyte proliferation and differentiation.
  • To investigate the molecular mechanisms by which Notch signaling regulates epidermal homeostasis.

Main Methods:

  • Keratinocyte-specific deletion of the Notch1 gene in vivo.
  • In vitro differentiation of primary keratinocytes.
  • Analysis of gene expression for differentiation markers and cell cycle regulators.
  • Chromatin immunoprecipitation to assess RBP-Jkappa binding to the p21 promoter.

Main Results:

  • Keratinocyte-specific Notch1 deletion led to epidermal hyperplasia and altered differentiation marker expression.
  • Endogenous Notch1 is essential for inducing p21WAF1/Cip1 expression in differentiating keratinocytes.
  • Activated Notch1 suppressed keratinocyte proliferation via RBP-Jkappa-dependent induction of p21WAF1/Cip1.
  • Activated Notch1 also induced early differentiation markers independently of RBP-Jkappa, involving Notch2 and the Notch1 cytoplasmic region.

Conclusions:

  • Notch signaling orchestrates keratinocyte growth arrest and differentiation through two distinct molecular pathways.
  • One pathway, dependent on RBP-Jkappa, regulates p21WAF1/Cip1 induction for growth suppression.
  • A second, RBP-Jkappa-independent pathway, mediated by Notch1 and Notch2, promotes early differentiation markers.

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