title: Integrin β4 regulation of PTHrP underlies its contribution to mammary gland development.
abstract: The integrin α6β4 (referred to as β4) is expressed in epithelial cells where it functions as a laminin receptor. Although in vitro studies have implicated β4 in the biology of mammary epithelial cells, its contribution to mammary gland development has not been settled. To address this problem, we generated and analyzed itgb4(flox/flox)MMTV-Cre(-) and itgb4(flox/flox)MMTV-Cre(+) mice. The salient features of embryonic mammary tissue from itgb4(flox/flox)MMTV-Cre(+) mice were significantly smaller mammary buds and increased apoptosis in the surrounding mesenchyme. Also, compared to control glands, the itgb4-deleted mammary buds lacked expression of the progenitor cell marker CK14 and they were unable to generate mammary glands upon transplantation into cleared fat pads of recipient mice. Analysis of mammary glands at puberty and during pregnancy revealed that itgb4-diminished mammary tissue was unable to elongate and undergo branching morphogenesis. Micro-dissection of epithelial cells in the mammary bud and of the surrounding mesenchyme revealed that loss of β4 resulted in a significant decrease in the expression of parathyroid hormone related protein (PTHrP) in epithelial cells and of target genes of the PTHrP receptor in mesenchymal cells. Given that the phenotype of the itgb4-deleted mammary tissue mimicked that of the PTHrP knockout, we hypothesized that β4 contributes to mammary gland development by sustaining PTHrP expression and enabling PTHrP signaling. Indeed, the inability of itgb4-deleted mammary buds to elongate was rescued by exogenous PTHrP. These data implicate a critical role for the β4 integrin in mammary gland development and provide a mechanism for this role.
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, United States.
authors.forename: Jiarong
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, United States.
authors.forename: Huayan
authors.initials: H
authors.lastname: Sun
authors.affiliation: Hunter James Kelly Research Institute, Departments of Biochemistry and Neurology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, United States.
authors.forename: M Laura
authors.initials: ML
authors.lastname: Feltri
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, United States.
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Mercurio
mesh_terms: D000818:Animals; D005260:Female; D017353:Gene Deletion; D039663:Integrin beta4 / Q000378:metabolism*; D008321:Mammary Glands, Animal / Q000254:growth & development* / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009929:Organ Size; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism*
chemical_list: D039663:Integrin beta4; D044162:Parathyroid Hormone-Related Protein