Ablation of beta1 integrin in mammary epithelium reveals a key role for integrin in glandular morphogenesis and differentiation.
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 beta1 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 beta1 integrin in vivo resulted in impaired alveologenesis and lactation. Cultured beta1 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. beta1 integrin-null mammary epithelial cells did not differentiate in response to prolactin stimulation because of defective Stat5 activation. In mice where beta1 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 beta1 integrins in prolactin signaling. This study demonstrates that beta1 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.
Naylor
Matthew J
MJ
Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, England, UK.
Li
Na
N
Cheung
Julia
J
Lowe
Emma T
ET
Lambert
Elise
E
Marlow
Rebecca
R
Wang
Pengbo
P
Schatzmann
Franziska
F
Wintermantel
Timothy
T
Schüetz
Günther
G
Clarke
Alan R
AR
Mueller
Ulrich
U
Hynes
Nancy E
NE
Streuli
Charles H
CH
D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion; D002454:Cell Differentiation; D002478:Cells, Cultured; D003433:Crosses, Genetic; D016207:Cytokines / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology*; D004848:Epithelium / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D019012:Integrin beta1 / Q000235:genetics* / Q000502:physiology*; D016023:Integrins / Q000378:metabolism; D007774:Lactation; D008321:Mammary Glands, Animal / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D011388:Prolactin / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
D016207:Cytokines; D019012:Integrin beta1; D016023:Integrins; D050799:STAT5 Transcription Factor; D011388:Prolactin; D048049:Extracellular Signal-Regulated MAP Kinases