Summary
A variety of cytokines mediate the activation of Janus protein tyrosine kinases (Jaks). The Jaks then phosphorylate cellular substrates, including members of the signal transducers and activators of transcription (Stat) family of transcription factors. Among the Stats, the two highly related proteins, Stat5a and Stat5b, are activated by a variety of cytokines. To assess the role of the Stat5 proteins, mutant mice were derived that have the genes deleted individually or together. The phenotypes of the mice demonstrate an essential, and often redundant, role for the two Stat5 proteins in a spectrum of physiological responses associated with growth hormone and prolactin. Conversely, the responses to a variety of cytokines that activate the Stat5 proteins, including erythropoietin, are largely unaffected.
Citations
Stephan Teglund, Catriona McKay, Erin Schuetz, Jan M. van Deursen, Dimitrios Stravopodis, Demin Wang, Michael Brown, Sara Bodner, Gerard Grosveld, James N. Ihle. Stat5a and Stat5b Proteins Have Essential and Nonessential, or Redundant, Roles in Cytokine Responses. Cell, Vol. 93, 841-850, May 29, 1998.Note: mice without a Stat 5a gene do not develop functional mammary tissue
Note: mice without a Stat 5b gene do not develop functional mammary tissue
Background
Cytokines regulate the proliferation and/or differentiated functions of cells through their interaction with receptors of the cytokine receptor superfamily. These receptors mediate their diverse effects through their ability to associate with and activate members of the Janus family of protein tyrosine kinases (Jaks). Among the substrates of the Jaks are members of the signal transducers and activators of transcription (Stat) family of proteins. The Stats are recruited to the receptor complexes through SH2 domain recognition of specific sites of receptor tyrosine phosphorylation, are phosphorylated by the Jaks, undergo dimerization, translocate to the nucleus, and affect the expression of a wide range of genes.
Seven mammalian Stat family members have been identified, many of which play highly specific roles in innate and acquired immunity. Stat1 is critical for interferon (IFN)-induced viral resistance. Similarly, Stat6 specifically mediates the effects of IL-4 or IL-13 on B or T cells, while Stat4 is critical for IL-12 signaling. The one possible exception is Stat3, which, when deleted, results in a very early embryonic lethality due to unknown deficiencies.
Stat5 was identified as a prolactin-induced mammary gland transcription factor. It was shown that two Stat5 genes encode proteins that are approximately 95% identical in amino acid sequence and that these two genes colocalized to murine chromosome 11, tightly linked to Stat3. The identity and chromosomal colocalization suggest that the two genes resulted from a recent gene duplication. Since both genes are expressed in a variety of cell types, it was anticipated that they would be functionally redundant.
Stat5a and Stat5b proteins are activated by tyrosine phosphorylation in response to a wide variety of cytokines. In addition to prolactin, Stat5 proteins are activated by growth hormone (GH), erythropoietin (Epo), thrombopoietin (Tpo), interleukin 3 (IL-3) and GM-CSF, and interleukin 2 (IL-2). In addition, the activation of the Stat5 proteins has been implicated in bcr/abl transformation and transformation of lymphocytes to factor independence.
To assess the role of the Stat5 proteins, we derived mice in which the two genes are individually and simultaneously mutated. Because of the identity of the two proteins, it was assumed they would be redundant in function. Indeed, it was quite unexpected to find phenotypes associated with the disruption of the individual genes as recently reported for Stat5a and, independently, for Stat5b. Our results support these findings but also demonstrate the loss of additional functions associated with growth hormone or prolactin. In addition, rather remarkably, the disruption of both genes failed to reveal a critical, nonredundant role in the response of a number of cytokines that activate the Stat5 proteins.
Results
Disruption of Stat5a or Stat5b Differentially Affect Mammary Gland
Development
Whole mammary gland mounts and histological sections are illustrated in Figure 1 for mature virgin mice of all mutant strains and for the lactating Stat5a and Stat5b mutant mice. As indicated below, female Stat5a/b mice are infertile and therefore could not be examined. As illustrated, the differentiation of ductal elements occurs in all the mutant mice comparable to wild-type mice. The major difference is the extent of development of terminal buds in all mutant mice. Following pregnancy, in response to prolactin, the alveolar development of the mammary gland is greatly amplified in wild-type mice (Figure 1C and Figure 1D). This expansion occurs relatively normally in Stat5b mice (Figure 1K and Figure 1L) but is dramatically reduced in Stat5a mice (Figure 1G and Figure 1H).
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