p190-B RhoGAP regulates mammary ductal morphogenesis

Mol Endocrinol. 2003 Jun;17(6):1054-65. doi: 10.1210/me.2002-0428. Epub 2003 Mar 13.


Previous studies from our laboratory have demonstrated that p190-B RhoGAP (p190-B) is differentially expressed in the Cap cells of terminal end buds (TEBs) and poorly differentiated rodent mammary tumors. Based on these observations we hypothesized that p190-B might play an essential role in invasion of the TEBs into the surrounding fat pad during ductal morphogenesis. To test this hypothesis, mammary development was studied in p190-B-deficient mice. A haploinsufficiency phenotype was observed in p190-B heterozygous mice as indicated by decreased number and rate of ductal outgrowth(s) at 3, 4, and 5 wk of age when compared with their wild-type littermates. This appeared to result from decreased proliferation in the Cap cells of the TEBs, a phenotype remarkably similar to that observed previously in IGF-I receptor null mammary epithelium. Furthermore, decreased expression of insulin receptor substrates 1 and 2 were observed in TEBs of p190-B heterozygous mice. These findings are consistent with decreased IGF signaling observed previously in p190-B-/- mouse embryo fibroblasts. To further assess if this defect was cell autonomous or due to systemic endocrine effects, the mammary anlagen from p190-B+/+, p190-B+/-, and p190-B-/- mice was rescued by transplantation into the cleared fat pad of recipient Rag1-/- mice. Surprisingly, as opposed to 75-80% outgrowths observed using wild-type donor epithelium, only 40% of the heterozygous and none of the p190-B-/- epithelial transplants displayed any outgrowths. Together, these results suggest that p190-B regulates ductal morphogenesis, at least in part, by modulating the IGF signaling axis.

Publication types

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

MeSH terms

  • Analysis of Variance
  • Animals
  • Cell Division / physiology
  • DNA-Binding Proteins
  • Female
  • GTPase-Activating Proteins
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / physiology*
  • Heterozygote
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Mammary Glands, Animal / cytology
  • Mammary Glands, Animal / growth & development*
  • Mammary Glands, Animal / metabolism
  • Mice
  • Morphogenesis
  • Nuclear Proteins / genetics
  • Nuclear Proteins / physiology*
  • Phosphoproteins / metabolism*
  • Repressor Proteins
  • Sexual Maturation / genetics
  • Sexual Maturation / physiology*
  • Signal Transduction
  • Somatomedins / metabolism*


  • Arhgap35 protein, mouse
  • Arhgap5 protein, mouse
  • DNA-Binding Proteins
  • GTPase-Activating Proteins
  • Guanine Nucleotide Exchange Factors
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Irs1 protein, mouse
  • Irs2 protein, mouse
  • Nuclear Proteins
  • Phosphoproteins
  • Repressor Proteins
  • Somatomedins