The Importance of Jak2 and Stat5 for Pregnancy-induced Cell Specification and Differentiation in the Mammary Gland

The Janus kinase 2 (Jak2) and the signal transducer and activator of transcription 5 (Stat5) are important intermediaries in “the lines of fire” of various growth factors that are implicated in normal mammary gland development.  Jak2 is a hormone-receptor-coupled kinase that mediates the tyrosine phosphorylation and activation of Stats, in particular Stat5a and Stat5b. The biological relevance of Jak2/Stat5 signaling in hormone-responsive adult tissues is difficult to investigate since deficiency in Jak2 or Stat5a/b leads to embryonic lethality. Therefore, we generated genetically-engineered animal models that lack Jak2 conditionally in mammary epithelial cells. The phenotypic analysis of these models shows that Jak2 is essential for mammogenesis in virgin, pregnant, and postpartum females. In addition to its pivotal role for mammary epithelial cell proliferation, specification, and differentiation, we demonstrate that this kinase is indispensable for the prolactin-mediated activation of Stat5 and maintenance of functionally differentiated alveolar cells during lactation.

A full-term pregnancy and the simultaneous activation of the Jak2/Stat5 pathway in response to prolactin signaling induce temporary and permanent changes in the mammary gland. One permanent change between mammary glands of nulliparous and parous females is the existence of unique epithelial cells (called PI-MECs) that originate during the first full-term pregnancy cycle. Parity-induced mammary epithelial cells (PI-MECs) are defined as a pregnancy hormone-responsive cell population that activates the promoter of late milk protein genes during the second half of pregnancy and lactation. However, unlike their terminally differentiated counterparts, these cells do not undergo programmed cell death during post-lactational remodeling of the gland. Upon transplantation into an epithelial-free mammary fat pad, PI-MECs exhibited two important features of multipotent mammary epithelial progenitors: a) self-renewal, and b) generation of diverse populations of ductal and alveolar cell types. Our recent studies show that these cells also express cell surface markers that are present on multipotent mammary epithelial stem cells. We propose that the unique developmental route that PI-MECs undergo during each pregnancy cycle is the basis for a general mechanism of selection and adaptation of alveolar cells to accomplish optimal functional differentiation and normal milk production.