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This Article Full Text Full Text (PDF) Supplemental Data Buy All Versions of this Article: fj.08-123398v1 fj.08-123398v2 fj.08-123398v3 23/10/3482    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by van Miltenburg, M. H. A. M. Articles by van de Water, B. PubMed PubMed Citation Articles by van Miltenburg, M. H. A. M. Articles by van de Water, B.

Complete focal adhesion kinase deficiency in the mammary gland causes ductal dilation and aberrant branching morphogenesis through defects in Rho kinase-dependent cell contractility

Martine H. A. M. van Miltenburg^*, Reshma Lalai^*, Hans de Bont^*, Eveline van Waaij^*, Hilary Beggs, Erik H. J. Danen^* and Bob van de Water^*,1

^* Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands; and

Department of Ophthalmology, University of California, San Francisco, California, USA

¹ Correspondence: Division of Toxicology, LACDR, Leiden University, Einsteinweg 55, P.O. Box 9502, 2300 RA Leiden, The Netherlands. E-mail: water_b{at}lacdr.leidenuniv.nl

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.—Van Miltenburg, M. H. A. M., Lalai, R., de Bont, H., van Waaij, E., Beggs, H., Danen, E. H. J., van de Water, B. Complete focal adhesion kinase deficiency in the mammary gland causes ductal dilation and aberrant branching morphogenesis through defects in ROCK-dependent cell contractility.

Key Words: adhesion signaling • lactation • myoepithelial cells • luminal epithelial cells