TMEM100: A Novel Intracellular Transmembrane Protein Essential for Vascular Development and Cardiac Morphogenesis

Abstract

Among members of the TGFβ superfamily, bone morphogenetic protein (BMP) 9 and BMP10 regulate vascular endothelium differentiation and morphogenesis by activating the specific receptor complex, which consists of ALK1 (or ACVRL1), BMPR2, and endoglin. Mutations in ACVRL1, BMPR2, or ENG are associated with hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension in humans [1, 2]. We previously identified TMEM100 as a downstream target gene of BMP9/BMP10-ALK1 signaling pathway [3]. TMEM100 is a novel intracellular protein with two putative transmembrane domains, and its amino acid sequence is highly conserved from fish to humans. To clarify the physiological significance of TMEM100, we generated Tmem100deficient mice and found that all mutant embryos died in utero around embryonic day 10.5 (E10.5). LacZ reporter driven by the Tmem100 locus was predominantly expressed in endothelial cells of developing arteries and endocardium. Tmem100 null embryos showed severe vascular dysmorphogenesis and cardiac enlargement at E9.5 and massive pericardial effusion and growth retardation at E10.5 (Fig. 21.1). These phenotypic abnormalities were virtually identical to those observed in Alk1/Acvrl1-deficient mice, suggesting that Tmem100 is an important downstream gene of BMP9/BMP10-ALK1 signaling during cardiovascular Note: This Chapter is also related to Part VI.

Sensitization of small‐diameter sensory neurons is controlled by TRPV1 and TRPA1 association

“…Moreover, ablation of the complex in spinal cord central terminals produced more pronounced anti-hypersensitivity than disruption of the complex in hind paws. 60,61 Alteration of sensitization levels within the A1-V1 complex could occur in two ways: activity dependent and activity independent. This implies that the reduction of sensitization occurs by attenuating neurotransmission at presynaptic levels more than by lowering receptor potentials in peripheral terminals.…”

“…Second, ablation or inhibition of Tmem100 could lead to significant side effects since it is critically important in other tissues. 60,61 Alteration of sensitization levels within the A1-V1 complex could occur in two ways: activity dependent and activity independent. Activity-dependent interactions between TRPA1 and TRPV1 channels often require sequential stimulation of TRPA1 and TRPV1.…”

“…First, Tmem100 expression levels in human DRG are relatively low. Second, ablation or inhibition of Tmem100 could lead to significant side effects since it is critically important in other tissues …”

The Role of a Lung Vascular Endothelium Enriched Gene TMEM100

“…Our recent study showed that overexpression of TMEM100 did not affect the EC cellular barrier integrity under the Thrombin challenge 13 , suggesting that the regulation of vascular permeability by Tmem100 in vivo might be due to the indirect regulation of extracellular matrix but not EC junction. In another study, Somekawa et al showed that Tmem100 null embryos showed fetal defects of arterial endothelium differentiation and severe vascular dysmorphogenesis and cardiac enlargement at E9.5 and massive pericardial effusion and growth retardation at E10.5 11,18 . These phenotypes are identical to the Acvrl1 deficiency mice 20 .…”

“…As a downstream target of the Bone Morphogenetic Protein (BMP) 9/10 and Activin-Like Kinase Receptor Type I (ALK1) signaling pathways 18 , TMEM100 plays an important role in angiogenesis, vascular morphogenesis, integrity and cardiovascular development. BMP9/10 acts mainly via an EC-specific ALK1 receptor and promote arterial endothelial maturation and quiescence.…”