p190-B RhoGAP regulates mammary ductal morphogenesis.

Abstract

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.

• Authors: Geetika Chakravarty, Darryl Hadsell, William Buitrago, Jeffrey Settleman, Jeffrey M Rosen
• Journal: Molecular endocrinology (Baltimore, Md.) (Mol Endocrinol) Vol. 17 Issue 6 Pg. 1054-65 (Jun 2003) ISSN: 0888-8809 [Print] United States
• PMID: 12637587 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 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

Topics

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