Abstract 9721: Tmem100, a Novel BMP9/10-Dependent Endothelial Gene Essential for Arterial Development and Morphogenesis
Introduction: Bone morphogenetic protein 9 (BMP9) and BMP10 play critical roles in regulating embryonic vascular development through their endothelium-specific ALK1 receptor. Mutations of the ALK1 gene cause human hereditary hemorrhagic telangiectasia and pulmonary hypertension, but their downstream functional proteins are largely unknown.
Methods and Results: We attempted to identify novel endothelial genes downstream of BMP9/10-ALK1 signaling by an mRNA microarray analysis of BMP9-treated human umbilical artery endothelial cells. BMP9 treatment activated expression of various known BMP9/10-regulated genes such as ID1 up to ten fold. Intriguingly, we also found that BMP9 markedly induced mRNA expression of a previously-uncharacterized gene TMEM100 more than 100-fold. siRNA knockdown experiments confirmed that TMEM100 expression by BMP9 or BMP10 was mediated by the ALK1 receptor activation. TMEM100 encodes a transmembrane protein that is highly conserved among species, but its expression profiles and physiological significance had not been studied. Tmem100 was co-expressed with Alk1 specifically in aortic endothelial cells of mouse embryos (figure, panel A). Tmem100 null mice die around E10.5 due to impaired differentiation of arterial endothelium and defects of vascular morphogenesis, which phenocopied vascular abnormalities observed in Alk1 null embryos, indicating a major role of Tmem100 in the BMP9/10-ALK1 signaling pathway (panel B). Furthermore, expression of activated Notch1 receptor, Notch1-ICD, as well as various Notch-target genes including Hey/Hrt transcription factors significantly decreased in Tmem100 null embryos, suggesting that Tmem100 is indispensable for regulation of Notch signaling in proper vascular development.
Conclusion: We identified Tmem100 to be a novel endothelial gene essential for arterial development and morphogenesis downstream of BMP9/10-ALK1 signaling.
- © 2011 by American Heart Association, Inc.