title: Jak2 is an essential tyrosine kinase involved in pregnancy-mediated development of mammary secretory epithelium.
abstract: 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.
authors.affiliation: Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. jonshi@helix.nih.gov
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Shillingford
authors.forename: Keiko
authors.initials: K
authors.lastname: Miyoshi
authors.forename: Gertraud W
authors.initials: GW
authors.lastname: Robinson
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Grimm
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Rosen
authors.forename: Hans
authors.initials: H
authors.lastname: Neubauer
authors.forename: Klaus
authors.initials: K
authors.lastname: Pfeffer
authors.forename: Lothar
authors.initials: L
authors.lastname: Hennighausen
mesh_terms: D000818:Animals; D001692:Biological Transport; D002454:Cell Differentiation; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000032:analysis / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology; D004848:Epithelium / Q000737:chemistry / Q000502:physiology; D005260:Female; D053614:Janus Kinase 2; D008321:Mammary Glands, Animal / Q000196:embryology / Q000502:physiology* / Q000637:transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D008894:Milk Proteins; D011247:Pregnancy; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D050799:STAT5 Transcription Factor; D028021:Sodium-Potassium-Chloride Symporters / Q000032:analysis; D015534:Trans-Activators / Q000032:analysis / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D050799:STAT5 Transcription Factor; D028021:Sodium-Potassium-Chloride Symporters; C494093:Stat5a protein, mouse; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2