Mammary epithelial-restricted expression of activated c-src rescues the block to mammary gland morphogenesis due to the deletion of the C-terminus of Patched-1

Mesenchymal dysplasia (mes) mice expressing a C-terminally truncated version of the Hedgehog (Hh)-ligand receptor, Patched-1 (Ptch1), exhibit a limited spectrum of developmental defects including blocked ductal morphogenesis of the mammary gland during puberty. Given that the Hh-ligands can stimulate signalling cascades distinct from the canonical pathway involving Smo and the Gli-family proteins and that Ptch1 binds to factors harbouring SH3-domains, we determined whether the mes mammary gland defect could be rescued by activating non-canonical signalling pathways downstream of Ptch1. We demonstrate here that expression of constitutively active c-src (c-srcAct) in mammary epithelial cells overcomes the block to mammary epithelial morphogenesis in mes mice. Specifically, MMTV-directed expression of c-srcAct rescued blocked ductal morphogenesis in mes mice, albeit only after animals were more than 15 weeks of age. The overall morphology resembled wild type mice expressing c-srcAct although 40% of mes/MMTV-c-srcAct mice exhibited terminal end buds at 24 weeks of age. C-srcAct restored the proliferative capacity of mes epithelial cells, self-renewal capacity of mammary progenitor cells and increased the expression of Esr1, Ptch1 and Gli1. These data reveal the cooperative interactions between signalling cascades involving c-src and Ptch1 and suggest that Hh-signalling may be permissive for c-src/Esr1-dependent mammary gland morphogenesis.

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► C-terminal deletion of Patched-1 completely blocks mammary gland morphogenesis.
► MMTV-c-srcAct rescues the block to ductal morphogenesis in mes mice.
► C-src induces expression of Esr1 as well as relocalization to the cytoplasm.
► C-src rescues self-renewal of mammary stem cells and induces Ptch1 and Gli1.
► These data reveal the cooperative interactions between c-src and Hh-signalling.