| First Author | Li J | Year | 2012 |
| Journal | Development | Volume | 139 |
| Issue | 19 | Pages | 3531-42 |
| PubMed ID | 22899851 | Mgi Jnum | J:187713 |
| Mgi Id | MGI:5437814 | Doi | 10.1242/dev.082222 |
| Citation | Li J, et al. (2012) Myocardin-like protein 2 regulates TGFbeta signaling in embryonic stem cells and the developing vasculature. Development 139(19):3531-42 |
| abstractText | 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/TGFbeta 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, TGFbeta expression, TGFbeta signaling and TGFbeta-regulated genes encoding ECM are downregulated in Mkl2(-/-) ES cells and the vasculature of Mkl2(-/-) embryos. The gene encoding TGFbeta2, the predominant TGFbeta 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 TGFbeta2 promoter. Moreover, Mkl2(-/-) ES cells exhibit derangements in cytoskeletal organization, cell adhesion and expression of ECM that are rescued by forced expression of TGFbeta2. Taken together, these data demonstrate that MKL2 regulates a conserved TGF-beta signaling pathway that is required for angiogenesis and ultimately embryonic survival. |
