Netrin-1/neogenin interaction stabilizes multipotent progenitor cap cells during mammary gland morphogenesis

Dev Cell. 2003 Mar;4(3):371-82. doi: 10.1016/s1534-5807(03)00054-6.


Netrin-1 and its receptors play an essential role patterning the nervous system by guiding neurons and axons to their targets. To explore whether netrin-1 organizes nonneural tissues, we examined its role in mammary gland morphogenesis. Netrin-1 is expressed in prelumenal cells, and its receptor neogenin is expressed in a complementary pattern in adjacent cap cells of terminal end buds (TEBs). We discovered that loss of either gene results in disorganized TEBs characterized by exaggerated subcapsular spaces, breaks in basal lamina, dissociated cap cells, and an increased influx of cap cells into the prelumenal compartment. Cell aggregation assays demonstrate that neogenin mediates netrin-1-dependent cell clustering. Thus, netrin-1 appears to act locally through neogenin to stabilize the multipotent progenitor (cap) cell layer during mammary gland development. Our results suggest that netrin-1 and its receptor neogenin provide an adhesive, rather than a guidance, function during nonneural organogenesis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Actins / metabolism
  • Animals
  • Apoptosis / physiology
  • Basement Membrane / metabolism
  • Basement Membrane / ultrastructure
  • Cadherins / metabolism
  • Cell Adhesion / genetics*
  • Cell Communication / genetics
  • Cell Differentiation / genetics*
  • Cells, Cultured
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism*
  • Female
  • Gene Expression Regulation, Developmental / genetics
  • Laminin / metabolism
  • Mammary Glands, Animal / abnormalities*
  • Mammary Glands, Animal / cytology
  • Mammary Glands, Animal / metabolism
  • Membrane Proteins / deficiency*
  • Membrane Proteins / genetics
  • Mice
  • Mice, Knockout
  • Mice, Nude
  • Multipotent Stem Cells / cytology
  • Multipotent Stem Cells / metabolism
  • Nerve Growth Factors / deficiency*
  • Nerve Growth Factors / genetics
  • Netrin-1
  • Stem Cell Transplantation
  • Stem Cells / cytology
  • Stem Cells / metabolism*
  • Tumor Suppressor Proteins


  • Actins
  • Cadherins
  • Laminin
  • Membrane Proteins
  • Nerve Growth Factors
  • Ntn1 protein, mouse
  • Tumor Suppressor Proteins
  • neogenin
  • Netrin-1