Myocardin-like protein 2 regulates TGF? signaling in embryonic stem cells and the developing vasculature.

ABSTRACT: The molecular mechanisms that regulate and coordinate signaling between the extracellular matrix (ECM) and cells contributing to the developing vasculature are complex and poorly understood. Myocardin-like protein 2 (MKL2) is a transcriptional co-activator that in response to RhoA and cytoskeletal actin signals physically associates with serum response factor (SRF), activating a subset of SRF-regulated genes. We now report the discovery of a previously undescribed MKL2/TGF? signaling pathway in embryonic stem (ES) cells that is required for maturation and stabilization of the embryonic vasculature. Mkl2(-/-) null embryos exhibit profound derangements in the tunica media of select arteries and arterial beds, which leads to aneurysmal dilation, dissection and hemorrhage. Remarkably, TGF? expression, TGF? signaling and TGF?-regulated genes encoding ECM are downregulated in Mkl2(-/-) ES cells and the vasculature of Mkl2(-/-) embryos. The gene encoding TGF?2, the predominant TGF? isoform expressed in vascular smooth muscle cells and embryonic vasculature, is activated directly via binding of an MKL2/SRF protein complex to a conserved CArG box in the TGF?2 promoter. Moreover, Mkl2(-/-) ES cells exhibit derangements in cytoskeletal organization, cell adhesion and expression of ECM that are rescued by forced expression of TGF?2. Taken together, these data demonstrate that MKL2 regulates a conserved TGF-? signaling pathway that is required for angiogenesis and ultimately embryonic survival.

SUBMITTER: Li J 

PROVIDER: S-EPMC3436110 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature