Abstract 9901: Essential Function of Tmem100 for Endothelial Differentiation and Vascular Development Downstream of ALK1 Signaling
Introduction: Among members of the TGFβ superfamily, bone morphogenetic protein (BMP) 9 and BMP10 regulate vascular development through activation of activin receptor-like kinase 1 (ALK1/ACVRL1) receptor. ALK1-mediated intracellular signaling is implicated in the etiopathogenesis of human diseases, but functional proteins downstream of ALK1 signaling are largely unknown. We previously reported that TMEM100, a gene encoding an intracellular transmembrane protein, is activated by BMP9 and BMP10 through ALK1 receptor. We further demonstrated that Tmem100 null mice showed embryonic lethality due to impaired differentiation of arterial endothelium and defects of vascular morphogenesis, which phenocopied most of vascular abnormalities observed in Alk1 null embryos. However, the mechanisms of vascular defects caused by the Tmem100 deficiency and responsible cell type remain to be investigated.
Methods and Results: To clarify which vascular cell type is contributed to developmental defects by the Tmem100 deletion, we generated Tmem100 conditional knockout mice using the Cre-loxP system. The deletion of endothelial Tmem100 caused impairment of vascular morphogenesis and embryonic lethality, which was virtually identical to the phenotypes of global null mice. To understand the mechanisms of vascular defects, we performed a microarray analysis using the yolk sac. We observed a significant decrease in the expression of Notch- and Akt-downstream genes, such as Hrt1/Hey1, Hrt2/Hey2, Klf2 and eNos, in Tmem100 null yolk sac as well as embryos. Expression of activated Notch1 receptor, Notch ICD, and Akt phosphorylation were down regulated in Tmem100 null yolk sac and embryos. Notch and Akt signaling regulates arterial development, and dysregulation of these signaling pathways was also observed in Alk1 null embryos, suggesting that TMEM100 works for proper vascular development downstream of ALK1 signaling, at least in part, by the regulation of these signaling pathways.
Conclusion: TMEM100 functions in endothelial cells play indispensable roles during vascular development and morphogenesis downstream of ALK1-mediated signaling.
- © 2012 by American Heart Association, Inc.