Ectodysplasin/NF-κB Promotes Mammary Cell Fate via Wnt/β-catenin Pathway

PLoS Genet. 2015 Nov 18;11(11):e1005676. doi: 10.1371/journal.pgen.1005676. eCollection 2015 Nov.

Abstract

Mammary gland development commences during embryogenesis with the establishment of a species typical number of mammary primordia on each flank of the embryo. It is thought that mammary cell fate can only be induced along the mammary line, a narrow region of the ventro-lateral skin running from the axilla to the groin. Ectodysplasin (Eda) is a tumor necrosis factor family ligand that regulates morphogenesis of several ectodermal appendages. We have previously shown that transgenic overexpression of Eda (K14-Eda mice) induces formation of supernumerary mammary placodes along the mammary line. Here, we investigate in more detail the role of Eda and its downstream mediator transcription factor NF-κB in mammary cell fate specification. We report that K14-Eda mice harbor accessory mammary glands also in the neck region indicating wider epidermal cell plasticity that previously appreciated. We show that even though NF-κB is not required for formation of endogenous mammary placodes, it is indispensable for the ability of Eda to induce supernumerary placodes. A genome-wide profiling of Eda-induced genes in mammary buds identified several Wnt pathway components as potential transcriptional targets of Eda. Using an ex vivo culture system, we show that suppression of canonical Wnt signalling leads to a dose-dependent inhibition of supernumerary placodes in K14-Eda tissue explants.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Ectodysplasins / biosynthesis
  • Ectodysplasins / genetics*
  • Ectodysplasins / metabolism
  • Embryo, Mammalian
  • Gene Expression Regulation, Developmental
  • Hair Follicle / growth & development
  • Humans
  • Mammary Glands, Human / cytology
  • Mammary Glands, Human / growth & development*
  • Mice
  • Morphogenesis / genetics*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Wnt Signaling Pathway / genetics*

Substances

  • Ectodysplasins
  • NF-kappa B

Grant support

This work was financially supported by grant 268798 of the Academy of Finland, Sigrid Jusélius Foundation, Jane and Aatos Erkko Foundation, Finnish Cancer Foundations all to MLM, and the Integrative Life Science Graduate Program of the University of Helsinki (MV and ET). PS is supported by grants of the Swiss National Science Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.