Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality

Abstract

Signal transducer and activator of transcription (STAT) proteins have been shown to mediate biological actions in response to cytokines. Stat3, a member of the STAT family, is activated by a variety of cytokines, including the interleukin 6 family of cytokines, leptin, granulocyte colonystimulating factor, and epidermal growth factor. To address the biological function of Stat3, we generated mice deficient in Stat3 by gene targeting. No viable Stat3-deficient mice could be obtained from heterozygote intercross. Analysis of embryos at several gestation times revealed that Stat3-deficient embryos showed a rapid degeneration between embryonic days 6.5 and 7.5, although they developed into the egg cylinder stage until embryonic day 6.0. These results demonstrate that Stat3 is essential for the early development of mouse embryos.Signal transducer and activator of transcription (STAT) proteins have been shown to play an important role in cytokine signaling pathways (1, 2). These proteins are tyrosinephosphorylated by Janus kinases after cytokine binding to its receptor. Once phosphorylated, STAT proteins form homo-or heterodimers, through interaction between the Src homology 2 domain and phosphorylated tyrosine, rapidly translocate to the nucleus and induce several gene expressions. Until now, six members of STAT family, Stat1 through Stat6, have been identified. Each member is shown to be activated by its specific cytokine and responsible for cytokine-mediated responses. Recent studies from mice deficient in several STAT family members have demonstrated that STAT proteins play an essential role in cytokine-mediated biological actions; Stat1 is critical for interferon-mediated actions and innate immunity (3, 4). Stat4 is essential for interleukin (IL)-12-mediated functions and Th1 cell differentiation, whereas Stat6 is for IL-4-mediated functions and Th2 cell differentiation (5-9).Stat3 was originally identified as acute phase response factor, which is activated by IL-6 family of cytokines (10,11). This molecule is shown to be important for IL-6-mediated biological effects on cultured cell lines (12,13). Further studies have demonstrated that Stat3 is activated in response to a variety of cytokines in addition to IL-6 family of cytokines. Stat3 is shown to be tyrosine-phosphorylated by granulocyte colony-stimulating factor and epidermal growth factor (EGF) in cultured cells (11,14). Furthermore, leptin, a hormone that regulates satiety and energy metabolism, has been shown to induce the activation of Stat3 in the hypothalamus (15). To examine the biological functions of Stat3, we have generated Stat3-deficient mice. MATERIALS AND METHODSGeneration of Stat3-Deficient Mice. The Stat3 genomic DNA was screened from 129͞Sv mouse genomic library, subcloned into pBluescript SK vector (Stratagene), and characterized by restriction enzyme mapping and DNA sequencing as described (16). A targeting vector was designed to replace a 3.0-kb genomic fragment containing exons 20, 21, and 22 with the pMC1-neo (Stratagene). The ...

Activation of Stat5 by platelet-derived growth factor (PDGF) is dependent on phosphorylation sites in PDGF β-receptor juxtamembrane and kinase insert domains

“…Studies on knockout mice show that Stat5a has an obligate role in mammary growth and di erentiation (Liu et al, 1997) and that Stat3 has a role in the early development of the mouse embryo (Takeda et al, 1997); but the roles of Stat3 and Stat5 in cytokineinduced proliferation remain to be determined.…”

STAT3 in immune responses and inflammatory bowel diseases

“…These cytokines are believed to play roles in development and normal functions of some important organs and tissues, such as heart, liver and lymphocyte differentiation. For example, disruption of gp130 leads to disorders in these systems and causes embryonic lethality [59]. Interestingly, more and more evidence have implicated STAT3 in myeloid differentiation.…”

“…Since classical knock-out (KO) of the STAT3 gene in mice resulted in early embryonic lethality [59], it was STAT3, immunity and inflammation 216 npg difficult to study physiological roles of STAT3 in mouse models. Various cell type specific STAT3 knockouts have been established including T-cells [60] and keratinocytes [61].…”

Frontal nasal prominence expression driven by Tcfap2a relies on a conserved binding site for STAT proteins

“…Homozygous deletion of Stat3, in mice, results in early embryonic lethality (Takeda et al, 1997), and thus, the contribution of Stat3 to craniofacial and limb bud development has not been assessed. Bones formed via either endochondral or intramembranous ossification in Stat1 Ϫ/Ϫ mice have an increase in mass and mineral density due to a disruption in the proliferation and differentiation properties of both osteoblasts and osteoclasts (Kim et al, 2003;Xiao et al, 2004), and FGFs have an anti-proliferative effect on chondrocytes that is disrupted by loss of Stat1 (Sahni et al, 1999(Sahni et al, , 2001.…”