Impaired alveologenesis and maintenance of secretory mammary epithelial cells in Jak2 conditional knockout mice

Kay-Uwe Wagner, Andrea Krempler, Aleata A. Triplett, Yongyue Qi, Nicholas M. George, Jianqiong Zhu, Hallgeir Rui

Research output: Contribution to journalArticle

114 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5510-5520
Number of pages11
JournalMolecular and cellular biology
Volume24
Issue number12
DOIs
StatePublished - Jun 1 2004

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Prolactin Receptors
Alveolar Epithelial Cells
Knockout Mice
Breast
Epithelial Cells
Transducers
Maintenance
Human Mammary Glands
Hormones
Mouse mammary tumor virus
Pregnancy
Morphogenesis
Lactation
Protein-Tyrosine Kinases
Genes
Exons
Lactic Acid
Intercellular Signaling Peptides and Proteins
Phosphorylation
Transplants

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Impaired alveologenesis and maintenance of secretory mammary epithelial cells in Jak2 conditional knockout mice. / Wagner, Kay-Uwe; Krempler, Andrea; Triplett, Aleata A.; Qi, Yongyue; George, Nicholas M.; Zhu, Jianqiong; Rui, Hallgeir.

In: Molecular and cellular biology, Vol. 24, No. 12, 01.06.2004, p. 5510-5520.

Research output: Contribution to journalArticle

Wagner, Kay-Uwe ; Krempler, Andrea ; Triplett, Aleata A. ; Qi, Yongyue ; George, Nicholas M. ; Zhu, Jianqiong ; Rui, Hallgeir. / Impaired alveologenesis and maintenance of secretory mammary epithelial cells in Jak2 conditional knockout mice. In: Molecular and cellular biology. 2004 ; Vol. 24, No. 12. pp. 5510-5520.
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