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United States Department of Agriculture

Agricultural Research Service

Title: Crosstalk between the p190-B RhoGAP and IGF signaling pathways is required for embryonic mammary bud development

item Heckman, Brandy
item Chakravarty, Geetika
item Vargo-gogola, Tracy
item Gonzales-rimbau, Maria
item Hadsell, Darryl
item Lee, Adrian
item Settleman, Jeffrey
item Rosen, Jeffrey

Submitted to: Developmental Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/3/2007
Publication Date: 9/1/2007
Citation: Heckman, B.M., Chakravarty, G., Vargo-Gogola, T., Gonzales-Rimbau, M., Hadsell, D.L., Lee, A.V., Settleman, J., Rosen, J.M. 2007. Crosstalk between the p190-B RhoGAP and IGF signaling pathways is required for embryonic mammary bud development. Developmental Biology. 309:137-149.

Interpretive Summary: In females, IGF-I is a growth factor that is important for the normal development of the mammary gland following puberty. However, this protein and the signaling molecules that it activates may also be important for early mammary gland development that occurs during the prenatal period in females. In this study, the IGF-I signaling pathway was studied during embryonic and fetal development in the mouse. The result demonstrated that the IGF-I signaling pathway needs to interact with another signaling pathway known as the p190-B/Rho/GAP pathway. This second signaling pathway allows cells to recognize their spatial location within a developing organ and helps them determine how they will contribute to the normal development of the organ. The studies highlight a previously unknown aspect of IGF-I action and may lead to future understanding of how IGF-I and other signaling pathways regulate normal mammary gland development in females.

Technical Abstract: P190-B RhoGAP (p190-B, also known as ARHGAP5) has been shown to play an essential role in invasion of the terminal end buds (TEBs) into the surrounding fat pad during mammary gland ductal morphogenesis. Here we report that embryos with a homozygous p190-B gene deletion exhibit major defects in embryonic mammary bud development. Overall, p190-B-deficient buds were smaller in size, contained fewer cells, and displayed characteristics of impaired mesenchymal proliferation and differentiation. Consistent with the reported effects of p190-B deletion on IGF-1R signaling, IGF-1R-deficient embryos also displayed a similar small mammary bud phenotype. However, unlike the p190-B-deficient embryos, the IGF-1R-deficient embryos exhibited decreased epithelial proliferation and did not display mesenchymal defects. Because both IGF and p190-B signaling affect IRS-1/2, we examined IRS-1/2 double knockout embryonic mammary buds. These embryos displayed major defects similar to the p190-B-deficient embryos including smaller bud size. Importantly, like the p190-B-deficient buds, proliferation of the IRS-1/2-deficient mesenchyme was impaired. These results indicate that IGF signaling through p190-B and IRS proteins is critical for mammary bud formation and ensuing epithelial-mesenchymal interactions necessary to sustain mammary bud morphogenesis.

Last Modified: 06/25/2017
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