Tmem100 , an ALK1 receptor signaling-dependent gene essential for arterial endothelium differentiation and vascular morphogenesis

Abstract

Members of the transforming growth factor-β superfamily play essential roles in various aspects of embryonic development and physiological organ function. Among them, bone morphogenetic protein (BMP) 9 and BMP10 regulate embryonic vascular development by activating their endothelial receptor ALK1 (activin receptor-like kinase 1, also called Acvrl1). ALK1-mediated intracellular signaling is implicated in the etiologies of human diseases, but their downstream functional proteins are largely unknown. In this study, we identified Tmem100 , a gene encoding a previously uncharacterized intracellular transmembrane protein, to be an embryonic endothelium-enriched gene activated by BMP9 and BMP10 through the ALK1 receptor. Tmem100 null mice showed embryonic lethality due to impaired differentiation of arterial endothelium and defects of vascular morphogenesis, which phenocopied most of the vascular abnormalities observed with the Acvrl1/Alk1 deficiency. The activity of Notch- and Akt-mediated signaling, which is essential for vascular development, was down-regulated in Tmem100 null mice. Cre -mediated deletion of Tmem100 in endothelial cells was sufficient to recapitulate the null phenotypes. These data indicated that TMEM100 may play indispensable roles downstream of BMP9/BMP10-ALK1 signaling during endothelial differentiation and vascular morphogenesis.

Impairment of endothelial‐mesenchymal transformation during atrioventricular cushion formation in Tmem100 null embryos

“…As we previously reported (Somekawa et al, 2012), all Tmem100 null embryos died before E11.0 in the present study. They started to show abnormal cardiac morphology from E9.5 ( Fig.…”

“…In addition, previous studies demonstrated Tmem100 expression not only in the embryonic heart and vasculature but also in the adult lung, prostate, kidney, and enteric neurons in humans or mice (van der Heul-Nieuwenhuijsen et al, 2006;Georgas et al, 2009;Moon et al, 2010;Somekawa et al, 2012;Eisenman et al, 2013). Studying Tmem100 actions in various organs will help find a new module of cellular signaling not only in cardiovascular development but also in other biological processes.…”

“…Since the Tmem100 expression is highly regulated by ALK1 receptor signaling (Somekawa et al, 2012), we also examined the expression pattern of lacZ reporter knocked into the Acvrl1/Alk1 locus (Alk1-lacZ). As previously reported (Oh et al, 2000;Urness et al, 2000), Alk1-lacZ reporter was specifically expressed in vascular endothelial cells of mouse embryos Fig.…”

“…The structure of the Tmem100 null allele and the sequence of genotyping primers were previously described (Somekawa et al, 2012). The exon 3 encoding the entire coding region of the Tmem100 gene was replaced with a lacZ reporter.…”

HIC2 Is a Novel Dosage-Dependent Regulator of Cardiac Development Located Within the Distal 22q11 Deletion Syndrome Region

“…Tmem100, also changed in our screen, is downstream of Bmp10 and is required in arterial endothelium. 43 Taken together, the human genetic and mouse genetic evidence implicate the transcription factor HIC2 as a contributor to the atypical 22q11DS phenotype. However, we do not discount the possibility of a combined haploinsufficiency of HIC2 with any or all of TBX1, CRKL, and MAPK1, depending on the size of the deletion.…”