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

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.

Molecular Mechanisms Guiding Embryonic Mammary Gland Development

“…There are likely also specific morphogenetic movements required by the epithelial cells for invagination of the bud. The mitotic index of the cells within the bud has been shown to be lower than that of the surrounding epidermal cells and, thus, the bud does not form as a result of cell division (Balinsky 1950;Propper 1978;Chu et al 2004;Heckman et al 2007). As with placode specification, the formation of the individual bud pairs display differential requirements for specific signaling pathways (Veltmaat et al 2006;Robinson 2007;Watson and Khaled 2008).…”

“…It is expressed primarily within the epithelium of the mammary bud at E12.5, but also at lower levels in the surrounding mesenchyme (Heckman et al 2007). P190-B 2/2 embryos have small mammary buds with a disorganized mammary mesenchyme that fails to express AR (Heckman et al 2007).…”

Extracellular Signal-Regulated Kinase Promotes Rho-Dependent Focal Adhesion Formation by Suppressing p190A RhoGAP

“…p190A contains an N-terminal GTPase domain, a large middle domain juxtaposed to the C-terminal GAP domain, and a short C-terminal tail (74). The C-terminal tail of ϳ50 amino acids is divergent between p190A and the closely related family member p190B (14) and thus may specify the unique functional roles for p190A and p190B revealed in gene knockout studies (10,11,41,77,78). p190A activity is dynamically regulated in response to external cues during cell adhesion and migration (5,6,59).…”

Identification of gene sets and pathways associated with lactation performance in mice

“…In previous studies, IGFBP5, one of the negative regulators of IGFR signaling has been proposed as a key regulator of mammary gland events during lactation and involution (10,57). The IGF signaling pathway has been demonstrated to play a central role in embryonic and postnatal mammary development, particularly in modulating mammary cell proliferation and differentiation, and as an inhibitor of apoptosis (23,26). IGF-1 transgenic animal models have demonstrated a positive effect of the IGF signaling pathway on maternal lactation performance (24).…”