Tmem100, an ALK1 receptor signaling-dependent gene essential for arterial endothelium differentiation and vascular morphogenesis.
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.
First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
Satoshi
S
Somekawa
Keiichi
K
Imagawa
Hisaki
H
Hayashi
Masahide
M
Sakabe
Tomoko
T
Ioka
Genki E
GE
Sato
Ken
K
Inada
Takaaki
T
Iwamoto
Toshio
T
Mori
Shiro
S
Uemura
Osamu
O
Nakagawa
Yoshihiko
Y
Saito
D030201:Activin Receptors, Type I / Q000378:metabolism*; D030301:Activin Receptors, Type II; D000818:Animals; D001158:Arteries / Q000166:cytology / Q000196:embryology*; D015152:Blotting, Northern; D015139:Blotting, Southern; D015153:Blotting, Western; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D055427:Growth Differentiation Factor 2 / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D046228:Microarray Analysis; D009024:Morphogenesis / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction
C119152:Bmp10 protein, mouse; D019485:Bone Morphogenetic Proteins; C526108:Gdf2 protein, mouse; D055427:Growth Differentiation Factor 2; D008565:Membrane Proteins; C556658:Tmem100 protein, mouse; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498931:Acvrl1 protein, mouse