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Published 21 November 2005. doi:10.1083/jcb.200503144
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 171, Number 4, 717-728
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Article

 Ablation of ß1 integrin in mammary epithelium reveals a key role for integrin in glandular morphogenesis and differentiation

Matthew J. Naylor1, Na Li2, Julia Cheung1, Emma T. Lowe1, Elise Lambert1, Rebecca Marlow1, Pengbo Wang1, Franziska Schatzmann1, Timothy Wintermantel3, Günther Schüetz3, Alan R. Clarke4, Ulrich Mueller5, Nancy E. Hynes2, and Charles H. Streuli1

1 Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, England, UK
2 Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland
3 Division of Molecular Biology of the Cell I, German Cancer Center, 69120 Heidelberg, Germany
4 Cardiff School of Biosciences, Cardiff University, Cardiff CF103US, Wales, UK
5 Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037

Correspondence to Matthew J. Naylor: m.naylor{at}victorchang.unsw.edu.au; or Charles H. Streuli: cstreuli{at}manchester.ac.uk

Integrin-mediated adhesion regulates the development and function of a range of tissues; however, little is known about its role in glandular epithelium. To assess the contribution of ß1 integrin, we conditionally deleted its gene in luminal epithelia during different stages of mouse mammary gland development and in cultured primary mammary epithelia. Loss of ß1 integrin in vivo resulted in impaired alveologenesis and lactation. Cultured ß1 integrin–null cells displayed abnormal focal adhesion function and signal transduction and could not form or maintain polarized acini. In vivo, epithelial cells became detached from the extracellular matrix but remained associated with each other and did not undergo overt apoptosis. ß1 integrin–null mammary epithelial cells did not differentiate in response to prolactin stimulation because of defective Stat5 activation. In mice where ß1 integrin was deleted after the initiation of differentiation, fewer defects in alveolar morphology occurred, yet major deficiencies were also observed in milk protein and milk fat production and Stat5 activation, indicating a permissive role for ß1 integrins in prolactin signaling. This study demonstrates that ß1 integrin is critical for the alveolar morphogenesis of a glandular epithelium and for maintenance of its differentiated function. Moreover, it provides genetic evidence for the cooperation between integrin and cytokine signaling pathways.

M.J. Naylor's present address is Developmental Biology Program, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia.

Abbreviations used in this paper: Adßgal, ß-galactosidase adenovirus; AdCre, Cre-recombinase adenovirus; Blg, ß lactoglobulin; BM, basement membrane; ILK, integrin-linked kinase; Prl, prolactin; Wap, whey acidic protein.


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