Neural fold closure defect (NTD) is one of the most common birth defects in humans, occurring at an average rate of 1 per 1000 pregnancies. Decreased maternal Mg2+ intake has been associated with an increased risk for NTD, suggesting a key role for Mg2+-permeant ion channels in this essential stage of development. Our research in Xenopus laevis has uncovered important roles for the TRPM6 and TRPM7 ion channels in gastrulation and neural fold closure during embryogenesis. Neural fold closure defects caused by depletion of TRPM7 from Xenopus laevis embryos can be prevented by Mg2+ supplementation or by expression of a Mg2+ transporter, supporting the hypothesis that Mg2+ and the ion channels that conduct this important cation play a critical role during this essential embryonic process. TRPM7 and TRPM6 are known to hetero-oligomerize when heterologously expressed in tissue culture cells, but reports vary as to whether TRPM6 functions by itself as a channel in vivo. Preliminary studies indicate that TRPM6 mRNA expression is upregulated during gastrulation and peaks during neurulation, supporting the hypothesis that the two channels are functioning together to regulate neural fold closure. We propose three specific aims to clarify the function and regulation of these two channels during early development. In the first specific aim, we will employ loss-of-function and gain-of-function experiments in Xenopus laevis to define the role of TRPM6 during development and its connection to the non-canonical Wnt pathway, which has been shown to regulate convergent extension movements during gastrulation and neural fold closure.
In specific aim 2 we will examine in Xenopus how TRPM6 and TRPM7 and its individual domains may be functioning together to regulate neural fold closure and how these channels may be impacting Mg2+ homeostasis in the developing embryo. Our research will also focus on how TRPM7's control of Mg2+ homeostasis is affecting the migratory behavior of cells.
In specific aim 3 we will investigate the role of 80K-H, a TRPM6- and TRPM7-interacting protein that functions synergistically with TRPM7 during gastrulation and neural fold closure, has in regulating these channels'protein levels, and determine how the Wnt pathway may be impacting this regulation. Collectively, the proposed experiments should greatly advance our understanding how these unique bifunctional channels are functioning in vivo, which could lead to new strategies for preventing neural tube closure defects as well as to new insights for combating the other pathological conditions for which these channels have been associated, including stroke and cancer.

Public Health Relevance

Neural tube defects, such as spina bifida, occur when the neural tube fails to close during embryogenesis and are the second most common birth defect;spina bifida alone affects 166,000 people in the United States with medical costs estimated to be over $70,000 annually for the first 20 years of life. Our research has shown that incubating developing embryos with excess magnesium prevents neural tube defects caused by loss of the TRPM7 ion channel, pointing to critical roles for magnesium and TRPM7 during early development. The proposed research will investigate the functions and regulations of the ion channels TRPM7 and TRPM6 as well as the role of magnesium during embryogenesis, which could help in the development of novel preventive strategies for these devastating birth defects.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Nie, Zhongzhen
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Medicine & Dentistry of NJ
Schools of Medicine
United States
Zip Code
Komiya, Yuko; Su, Li-Ting; Chen, Hsiang-Chin et al. (2014) Magnesium and embryonic development. Magnes Res 27:1-8
Decker, Amanda R; McNeill, Matthew S; Lambert, Aaron M et al. (2014) Abnormal differentiation of dopaminergic neurons in zebrafish trpm7 mutant larvae impairs development of the motor pattern. Dev Biol 386:428-39
Liu, Wei; Su, Li-Ting; Khadka, Deepak K et al. (2011) TRPM7 regulates gastrulation during vertebrate embryogenesis. Dev Biol 350:348-57
Su, Li-Ting; Liu, Wei; Chen, Hsiang-Chin et al. (2011) TRPM7 regulates polarized cell movements. Biochem J 434:513-21
Tsai, Yu-Chen; Pestka, Sidney; Wang, Lu-Hai et al. (2011) Interferon-* signaling contributes to Ras transformation. PLoS One 6:e24291
Chen, Hsiang-Chin; Xie, Jia; Zhang, Zheng et al. (2010) Blockade of TRPM7 channel activity and cell death by inhibitors of 5-lipoxygenase. PLoS One 5:e11161
Su, Li-Ting; Chen, Hsiang-Chin; Gonzalez-Pagan, Omayra et al. (2010) TRPM7 activates m-calpain by stress-dependent stimulation of p38 MAPK and c-Jun N-terminal kinase. J Mol Biol 396:858-69