Basal Cell Signaling by p63 Controls Luminal Progenitor Function and Lactation via NRG1

Dev Cell. 2014 Jan 27;28(2):147-60. doi: 10.1016/j.devcel.2013.11.019. Epub 2014 Jan 9.

Abstract

The mammary epithelium is organized as a bilayer of luminal and basal/myoepithelial cells. During pregnancy, the luminal compartment expands for milk production, while basal cells are thought to provide structural and contractile support. Here, we reveal a pregnancy-specific role of basal epithelia as a central coordinator of lactogenesis. We demonstrate that genetic deletion of the transcription factor p63 (Trp63) gene exclusively within basal cells of the adult gland during pregnancy leads to dramatic defects in luminal cell proliferation and differentiation, resulting in lactation failure. This phenotype is explained by direct transcriptional activation of the epidermal growth factor family ligand gene Nrg1 by p63 selectively in basal cells, which is required for luminal ERBB4/STAT5A activation and consequent luminal progenitor cell maturation. Thus, paracrine basal-to-luminal cell signaling, controlled by p63 via NRG1, orchestrates the entire lactation program. Collectively, these findings redefine the paradigm for cellular interactions specifying the functional maturation of the mammary gland.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult Stem Cells / cytology
  • Adult Stem Cells / metabolism*
  • Adult Stem Cells / physiology
  • Animals
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Proliferation
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism*
  • Epithelial Cells / physiology
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Female
  • Gene Deletion
  • HEK293 Cells
  • Humans
  • Lactation*
  • Mammary Glands, Animal / cytology
  • Mammary Glands, Animal / physiology
  • Mice
  • Neuregulin-1 / genetics
  • Neuregulin-1 / metabolism*
  • Paracrine Communication
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Pregnancy / metabolism
  • Receptor, ErbB-4
  • STAT5 Transcription Factor / genetics
  • STAT5 Transcription Factor / metabolism
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcriptional Activation

Substances

  • Neuregulin-1
  • Nrg1 protein, mouse
  • Phosphoproteins
  • STAT5 Transcription Factor
  • Stat5a protein, mouse
  • Trans-Activators
  • Trp63 protein, mouse
  • ERBB4 protein, human
  • ErbB Receptors
  • Erbb4 protein, mouse
  • Receptor, ErbB-4