SLIT/ROBO1 signaling suppresses mammary branching morphogenesis by limiting basal cell number

Dev Cell. 2011 Jun 14;20(6):827-40. doi: 10.1016/j.devcel.2011.05.012.

Abstract

In the field of breast biology, there is a growing appreciation for the "gatekeeping function" of basal cells during development and disease processes yet mechanisms regulating the generation of these cells are poorly understood. Here, we report that the proliferation of basal cells is controlled by SLIT/ROBO1 signaling and that production of these cells regulates outgrowth of mammary branches. We identify the negative regulator TGF-β1 upstream of Robo1 and show that it induces Robo1 expression specifically in the basal layer, functioning together with SLIT2 to restrict branch formation. Loss of SLIT/ROBO1 signaling in this layer alone results in precocious branching due to a surplus of basal cells. SLIT2 limits basal cell proliferation by inhibiting canonical WNT signaling, increasing the cytoplasmic and membrane pools of β-catenin at the expense of its nuclear pool. Together, our studies provide mechanistic insight into how specification of basal cell number influences branching morphogenesis.

Publication types

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

MeSH terms

  • Animals
  • Axin Protein
  • Blotting, Western
  • Cell Adhesion
  • Cell Movement
  • Cell Proliferation*
  • Cytoskeletal Proteins / physiology
  • Female
  • Forkhead Transcription Factors / physiology
  • Intercellular Signaling Peptides and Proteins / physiology*
  • Mammary Glands, Animal / cytology
  • Mammary Glands, Animal / metabolism*
  • Membrane Proteins / physiology*
  • Mice
  • Mice, Knockout
  • Mice, Nude
  • Morphogenesis
  • Nerve Tissue Proteins / physiology*
  • RNA, Messenger / genetics
  • Receptors, Immunologic / physiology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism*
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • Axin Protein
  • Axin2 protein, mouse
  • Cytoskeletal Proteins
  • Forkhead Transcription Factors
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • RNA, Messenger
  • Receptors, Immunologic
  • Slit1 protein, mouse
  • Slit3 protein, mouse
  • Transforming Growth Factor beta1
  • Whn protein
  • Wnt Proteins
  • beta Catenin
  • roundabout protein
  • Slit homolog 2 protein