Ablation of beta 1 integrin, focal adhesion kinase and integrin linked kinase in mammary epithelium reveals a critical role for integrin in glandular morphogenesis and differentiation [Abstract]

Integrin mediated cell-matrix 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 b1 integrin, we conditionally deleted it from luminal epithelia during different stages of mammary gland development, and in cultured primary mammary epithelial cells. Loss of b1 integrin prior to pregnancy resulted in impaired alveologenesis and lactation. Cultured b1 integrin null cells displayed abnormal focal adhesion function, signal transduction, and could not form or maintain polarised acini. In vivo, epithelial cells became detached from the ECM, but remained associated with each other and did not undergo overt apoptosis. Deletion of b1 integrin following mammary differentiation also resulted in impaired lactation, and b1 integrin null cells failed to differentiate in response to prolactin stimulation, due to defective Stat5 activation. To further define the components mediating the effects of b1 integrin, we conditional inactivated two key integrin signalling molecules, focal adhesion kinase (Fak) and integrin linked kinase (Ilk) using the same methodologies. Deletion of these proteins resulted in the recapitulation of different aspects of integrin function. Fak ablation caused defects in lobuloalveolar development and epithelial proliferation, while Ilk deletion resulted in cell detachment defects. These data demonstrate that b1 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 crosstalk between integrin and cytokine signalling pathways, and begins to dissect the different components mediating integrin function in glandular epithelium.