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Molecular Endocrinology 16 (3): 563-570
Copyright © 2002 by The Endocrine Society

Jak2 Is an Essential Tyrosine Kinase Involved in Pregnancy-Mediated Development of Mammary Secretory Epithelium

Jonathan M. Shillingford, Keiko Miyoshi, Gertraud W. Robinson, Sandra L. Grimm, Jeffrey M. Rosen, Hans Neubauer, Klaus Pfeffer and Lothar Hennighausen

Laboratory of Genetics and Physiology (J.M.S., K.M., G.W.R., L.H.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; Department of Molecular and Cellular Biology (S.L.G., J.M.R.), Baylor College of Medicine; Houston, Texas 77030; and Institute of Medical Microbiology (H.N., K.P.), Immunology, and Hygiene, Technical University of Munich, D-81675 Munich, Germany

Address all correspondence and requests for reprints to: Dr. Jonathan Shillingford, Laboratory of Genetics and Physiology, National Institutes of Health, 9000 Rockville Pike, Room 105, Building 8, Bethesda, Maryland 20817. E-mail: jonshi{at}helix.nih.gov.

The PRL receptor (PrlR) and the signal transducer and activator of transcription 5a (Stat5a) are essential for the proliferation and differentiation of mammary epithelium during pregnancy. Based on tissue culture cell experiments, Jak2 is the tyrosine kinase responsible for the phosphorylation of both the PrlR and Stat5. We have now used a genetic approach to test the role of Jak2 in the mammary gland, a PrlR-responsive tissue. Because Jak2-null embryos die at E12.5, we transplanted Jak2-null mammary anlagen into cleared fat pads of wild-type mice and investigated epithelial development during pregnancy. In the absence of Jak2, no secretory alveoli were present at parturition, and epithelial cell proliferation was reduced by 95% after an acute hormone treatment. Furthermore, the Na-K-Cl cotransporter, a ductal marker, was maintained in Jak2-null epithelium and the sodium-phosphate cotransporter type IIb, a secretory cell marker, was absent. Nuclear Stat5a was only observed in a few epithelial cells in Jak2-null glands at pregnancy and parturition compared with most epithelial cells in wild-type glands. Taken together, our results demonstrate that Jak2 is a critical tyrosine kinase that conveys intracellular signals necessary for proliferation and differentiation of mammary epithelium during pregnancy.




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