title: 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.
abstract: 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-src(Act)) in mammary epithelial cells overcomes the block to mammary epithelial morphogenesis in mes mice. Specifically, MMTV-directed expression of c-src(Act) 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-src(Act) although 40% of mes/MMTV-c-src(Act) mice exhibited terminal end buds at 24 weeks of age. C-src(Act) 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.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Canada.
authors.forename: Hong
authors.initials: H
authors.lastname: Chang
authors.forename: Laurent
authors.initials: L
authors.lastname: Balenci
authors.forename: Nadia
authors.initials: N
authors.lastname: Okolowsky
authors.forename: William J
authors.initials: WJ
authors.lastname: Muller
authors.forename: Paul A
authors.initials: PA
authors.lastname: Hamel
mesh_terms: D000818:Animals; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D053823:Hedgehog Proteins / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000254:growth & development*; D051379:Mice; D008810:Mice, Inbred C57BL; D009024:Morphogenesis; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000071676:Zinc Finger Protein GLI1; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D047628:Estrogen Receptor alpha; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D000071676:Zinc Finger Protein GLI1; D019061:src-Family Kinases