BMP-mediated induction of GATA4/5/6 blocks somitic responsiveness to SHH

Abstract

The relative timing of SHH and BMP signals controls whether presomitic mesoderm (PSM) cells will adopt either a chondrogenic or lateral plate mesoderm fate. Here we document that SHH-mediated induction of Nkx3.2 maintains the competence of somitic cells to initiate chondrogenesis in response to subsequent BMP signals by repressing BMP-dependent induction of GATA genes. Conversely, administration of BMP signals to PSM or forced expression of GATA family members in chick PSM explants blocks induction of hedgehogdependent gene expression. We demonstrate that GATA factors can interact with Gli factors and can recruit the transcriptional co-factor FOG1 (ZFPM1) to the regulatory region of the mouse Gli1 gene, repressing the induction of Gli1 by SHH by binding to both GATA and Gli binding sites. Knockdown of FOG1 reverses the ability of GATA factors to repress Gli1 expression. Our findings uncover a novel role for GATA transcription factors as repressors of hedgehog signaling, and document that NKX3.2 maintains the ability of sclerotomal cells to express SHH transcriptional targets in the presence of BMP signals by repressing the induction of Gata4/5/6.

GATA4 and GATA6 regulate pancreatic endoderm identity through inhibition of hedgehog signaling

“…In addition, there was a notable upregulation of many components of the hedgehog pathway, suggesting that the major mechanism of GATA4/6-regulated pancreas development is through suppression of the hedgehog pathway. Previous studies have demonstrated that GATA factors can negatively regulate Shh expression in the stomach, limb bud, and somites (Daoud et al, 2014;Jacobsen et al, 2005;Kozhemyakina et al, 2014). Our studies suggest that GATA4 and GATA6 pattern the foregut endoderm through the repression of hedgehog signaling.…”

“…During gastric development, Gata4 and Shh expression is mutually exclusive, suggesting that GATA4 might inhibit the expression of Shh (Jacobsen et al, 2005). In the limb bud, GATA6 was shown to inhibit Shh gene expression through a limb bud-specific enhancer of the Shh gene , and in the somitic system, GATA4/5/6 were found to inhibit Shh signaling by inhibiting Gli1 expression, although direct inhibition of Shh was not required (Daoud et al, 2014). The upregulation of hedgehog pathway expression in the pDKO mice suggested that Shh might be repressed by GATA4 and/or GATA6.…”

Hedgehog pathway activation in T-cell acute lymphoblastic leukemia predicts response to SMO and GLI1 inhibitors

“…GATA1/2 transcription factors have known binding sites in the GLI1 and SHH promoters, 42 and GATA6 is known to suppress the SHH gene in limb development. 43,44 Using chromatin immunoprecipitation, we confirmed binding of GATA1 to 2 predicted regions of the GLI1 promoter in HSB2, a T-ALL cell line that expresses GATA1 (supplemental Figure 4). In addition, NF-kB2 was found to be positively correlated with SHH, IHH, and GLI1 expression (supplemental Figure 3).…”

A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation

“…Nkx3-2 is a BMP-dependent transcriptional repressor (Kim and Lassar, 2003) that blocks the expression of inhibitor(s) of Sox9 transcription (Zeng et al, 2002). It was recently found that Nkx3-2 blocks BMPdependent expression of several GATA transcription factors (Gata4, Gata5 and Gata6) in explants of paraxial mesoderm, and that these GATA factors can in turn block Shh-dependent induction of Sox9 gene expression (Daoud et al, 2014) (Fig. 3).…”