Crosstalk between the p190-B RhoGAP and IGF signaling pathways is required for embryonic mammary bud development.
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.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Brandy M
BM
Heckman
Geetika
G
Chakravarty
Tracy
T
Vargo-Gogola
Maria
M
Gonzales-Rimbau
Darryl L
DL
Hadsell
Adrian V
AV
Lee
Jeffrey
J
Settleman
Jeffrey M
JM
Rosen
D000818:Animals; D004848:Epithelium / Q000196:embryology / Q000502:physiology; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008321:Mammary Glands, Animal / Q000196:embryology* / Q000378:metabolism; D008648:Mesoderm / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
C513042:Arhgap5 protein, mouse; D020690:GTPase-Activating Proteins; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D010750:Phosphoproteins; D017526:Receptor, IGF Type 1