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.
Note: This Chapter is also related to Part VI.
You have full access to this open access chapter, Download chapter PDF
Similar content being viewed by others
Keywords
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 Tmem100-deficient 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 development. We also demonstrated that Tmem100 null embryos showed atrioventricular canal cushion formation defect, indicating Tmem100 works also as an important factor for valve and septum morphogenesis.
Taken together, our studies indicate that TMEM100 is a novel endothelial-specific protein for cardiovascular morphogenesis downstream of BMP9/BMP10-ALK1 signaling. Clarifying the function of TMEM100 will lead to a better understanding of the mechanisms of cardiovascular morphogenesis and the etiologies of human congenital diseases.
References
Govani FS, Shovlin CL. Hereditary haemorrhagic telangiectasia: a clinical and scientific review. Eur J Hum Genet. 2009;17:860–71.
Lowery JW, de Caestecker MP. BMP signaling in vascular development and disease. Cytokine Growth Factor Rev. 2010;21:287–98.
Somekawa S, et al. Tmem100, an ALK1 receptor signaling-dependent gene essential for arterial endothelium differentiation and vascular morphogenesis. Proc Natl Acad Sci U S A. 2012;109:12064–9.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Open Access This chapter is distributed under the terms of the Creative Commons Attribution-Noncommercial 2.5 License (http://creativecommons.org/licenses/by-nc/2.5/), which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. The images or other third party material in this chapter are included in the work's Creative Commons license, unless indicated otherwise in the credit line; if such material is not included in the work's Creative Commons license and the respective action is not permitted by statutory regulation, users will need to obtain permission from the license holder to duplicate, adapt or reproduce the material.
Copyright information
© 2016 The Author(s)
About this chapter
Cite this chapter
Mizuta, K., Sakabe, M., Somekawa, S., Saito, Y., Nakagawa, O. (2016). TMEM100: A Novel Intracellular Transmembrane Protein Essential for Vascular Development and Cardiac Morphogenesis. In: Nakanishi, T., Markwald, R., Baldwin, H., Keller, B., Srivastava, D., Yamagishi, H. (eds) Etiology and Morphogenesis of Congenital Heart Disease. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54628-3_21
Download citation
DOI: https://doi.org/10.1007/978-4-431-54628-3_21
Published:
Publisher Name: Springer, Tokyo
Print ISBN: 978-4-431-54627-6
Online ISBN: 978-4-431-54628-3
eBook Packages: MedicineMedicine (R0)