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)
|