title: Complete focal adhesion kinase deficiency in the mammary gland causes ductal dilation and aberrant branching morphogenesis through defects in Rho kinase-dependent cell contractility.
abstract: The adult, virgin mammary gland is a highly organized branched ductal network comprising two major cell types: myoepithelial and luminal epithelial cells. To study the role and mechanism of focal adhesion kinase (FAK)-mediated signaling in mammary gland development and differentiation, we used a conditional Fak-knockout mammary epithelial cell (MEC) transplantation model. Conditional Cre recombinase (Cre)-mediated Fak deletion in primary cultured MECs isolated from FAK(lox/lox)/Rosa26Cre-ERT2 donor mice caused loss of FAK in all mammary cells. Transplantation of Fak-knockout MECs in a cleared mammary fat pad of immune-deficient recipient mice resulted in development of new but dilated virgin ducts with a disrupted myoepithelial and luminal epithelial cell multilayer and aberrant ductal morphogenesis during pregnancy. In the absence of FAK, MECs spread poorly, showed enhanced Rho kinase (ROCK)-mediated cytoskeletal contractility, and failed to respond to receptor-mediated cytoskeletal remodeling. Likewise, FAK deficiency fully inhibited branching morphogenesis of mammary gland organoids in a ROCK-dependent manner. Altogether these data suggest a model in which FAK coordinates contractile forces in MECs to maintain the bilayered cellular organization of myoepithelial and luminal epithelial cells in ducts, thus allowing proper mammary gland development and function.
authors: Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, Einsteinweg 55, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors: Martine H A M
authors: MH
authors: van Miltenburg
authors: Reshma
authors: R
authors: Lalai
authors: Hans
authors: H
authors: de Bont
authors: Eveline
authors: E
authors: van Waaij
authors: Hilary
authors: H
authors: Beggs
authors: Erik H J
authors: EH
authors: Danen
authors: Bob
authors: B
authors: van de Water
mesh_terms: D000818:Animals; D004847:Epithelial Cells / Q000201:enzymology / Q000502:physiology; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000502:physiology*; D017353:Gene Deletion; D007774:Lactation / Q000235:genetics; D008321:Mammary Glands, Animal / Q000002:abnormalities / Q000254:growth & development* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis / Q000235:genetics; D011247:Pregnancy; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D054460:rho-Associated Kinases