Lobuloalveolar proliferation and differentiation of the mammary gland during pregnancy requires the coordinated action of steroid and peptide hormones. In the cast of characters, prolactin (PRL) appears to be a central player in the promotion of mammopoesis and lactogenesis. Binding of PRL to the PRL receptor (PRLR) induces receptor dimerization and activation of the Janus kinase 2 (JAK2). JAK2 in turn phosphorylates transcription factors which belong to the family of signal transducers and activators of transcription (STAT). Phosphorylation of specific tyrosine residues confers DNA binding activity to STAT proteins and results in the transcriptional activation of genes containing g-interferon activation sites (GAS). PRL has been shown in tissue culture cells to signal through Stat 1, 3 and 5 and to activate promoters containing the b-casein gene GAS site. In the functional post-partum mammary gland high levels of activated Stat5 can be found while only small amounts of phosphorylated Stat1 and Stat3 are found. The two isoforms of Stat5 (5a and 5b) show 96% similarity and form heterodimers upon phosphorylation. Phosphorylation of both isoforms is very low in mammary tissue of virgins and during early pregnancy, but rises sharply after day 14 of pregnancy, supporting the hypothesis that Stat5 is necessary for alveolar proliferation and differentiation. Although Stat5a and Stat5b are homologous, it is unclear whether their functions are purely redundant, or unique in some respects. The only profound difference between Stat5a and Stat5b is within their C-termini, which encompass a transcriptional activator sequence . The role of Stat5a in development was addressed in mice from which the Stat5b gene had been deleted using homologous recombination. Stat5b deficient mice developed functional mammary tissue during pregnancy and they were able to nurse their young. In contrast, in Stat5a-deficient mice mammary development was impaired and females failed to lactate. These results demonstrate that the presence of Stat5b is not required for functional mammary gland development. However, the presence of Stat5a is mandatory for mammary growth and differentiation. These findings reveal an unexpected level of specificity of the two Stat5 isoforms when activated under physiological conditions.
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Note: mice without a Stat5a gene do not develop functional mammary tissue (Stat5a-null mice). See also mice without a Stat5a and Stat5b gene (Stat5ab-null)