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Molecular and Cellular Biology, June 2004, p. 5510-5520, Vol. 24, No. 12
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.12.5510-5520.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Impaired Alveologenesis and Maintenance of Secretory Mammary Epithelial Cells in Jak2 Conditional Knockout Mice

Kay-Uwe Wagner,1* Andrea Krempler,1,{dagger} Aleata A. Triplett,1 Yongyue Qi,1 Nicholas M. George,1 Jianqiong Zhu,2 and Hallgeir Rui2

Eppley Institute for Research in Cancer and Allied Diseases and Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-6805,1 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D.C. 20057-14692

Received 29 December 2003/ Returned for modification 21 February 2004/ Accepted 20 March 2004

Jak2 is a hormone-receptor-coupled kinase that mediates the tyrosine phosphorylation and activation of signal transducers and activators of transcription (Stat). The biological relevance of Jak2-Stat signaling in hormone-responsive adult tissues is difficult to investigate since Jak2 deficiency leads to embryonic lethality. We generated Jak2 conditional knockout mice to study essential functions of Jak2 during mammary gland development. The mouse mammary tumor virus-Cre-mediated excision of the first coding exon resulted in a Jak2 null mutation that uncouples signaling from the prolactin receptor (PRL-R) to its downstream mediator Stat5 in the presence of normal and supraphysiological levels of PRL. Jak2-deficient females were unable to lactate as a result of impaired alveologenesis. Unlike Stat5a knockouts, multiple gestation cycles could not reverse the Jak2-deficient phenotype, suggesting that neither other components of the PRL-R signaling cascade nor other growth factors and their signal transducers were able to compensate for the loss of Jak2 function to activate Stat5 in vivo. A comparative analysis of Jak2-deficient mammary glands with transplants from Stat5a/b knockouts revealed that Jak2 deficiency also impairs the pregnancy-induced branching morphogenesis. Jak2 conditional mutants therefore resemble PRL-R knockouts more closely, which suggested that Jak2 deficiency might affect additional PRL-R downstream mediators other than Stat5a and Stat5b. To address whether Jak2 is required for the maintenance of PRL-responsive, differentiating alveolar cells, we utilized a transgenic strain that expresses Cre recombinase under regulatory elements of the whey acidic protein gene (Wap). The Wap-Cre-mediated excision of Jak2 resulted in a negative selection of differentiated alveolar cells, suggesting that Jak2 is required not only for the proliferation and differentiation of alveolar cells but also for their maintenance during lactation.

* Corresponding author. Mailing address: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Rm. 8009, Omaha, NE 68198-6805. Phone: (402) 559-3288. Fax: (402) 559-4651. E-mail: kuwagner{at}unmc.edu.

{dagger} Present address: Department of Medical Biochemistry and Molecular Biology, University of the Saarland, Homburg 66424, Germany.

Molecular and Cellular Biology, June 2004, p. 5510-5520, Vol. 24, No. 12
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.12.5510-5520.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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