p190-B RhoGAP regulates mammary ductal morphogenesis.
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.
Chakravarty
Geetika
G
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Hadsell
Darryl
D
Buitrago
William
W
Settleman
Jeffrey
J
Rosen
Jeffrey M
JM
D000704:Analysis of Variance; D000818:Animals; D002455:Cell Division / Q000502:physiology; D004268:DNA-Binding Proteins; D005260:Female; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000502:physiology*; D006579:Heterozygote; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008321:Mammary Glands, Animal / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D051379:Mice; D009024:Morphogenesis; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism*; D012097:Repressor Proteins; D012741:Sexual Maturation / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D013002:Somatomedins / Q000378:metabolism*
C513041:Arhgap35 protein, mouse; C513042:Arhgap5 protein, mouse; D004268:DNA-Binding Proteins; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D009687:Nuclear Proteins; D010750:Phosphoproteins; D012097:Repressor Proteins; D013002:Somatomedins