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MARK2/Par1b Insufficiency Attenuates DVL Gene Transcription via Histone Deacetylation in Lumbosacral Spina Bifida

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Abstract

Dishevelled (DVL/Dvl) genes play roles in canonical and noncanonical Wnt signaling, both of which are essential in neural tube closing and are involved in balancing neural progenitor growth and differentiation, or neuroepithelial cell polarity, respectively. In mouse Dvl haploinsufficiency leads to neural tube defects (NTDs), which represent the second most common birth defects. However, DVL genes’ genetic contributions in human NTDs are modest. We sought to explore the molecular impact on such genes in human NTDs in a Han Chinese cohort. In 47 cases with NTDs and 61 matched controls, in brain tissues, the DVL1/2 mRNA levels were correlated with the levels of a serine/threonine protein kinase MARK2, and in 20 cases with lumbosacral spina bifida, the mRNA levels of DVL1 and MARK2 were significantly decreased; by contrast, only an intronic rare variant was found. Moreover, in an extended population, we found merely three novel rare missense variants in 1 % of individuals with NTDs. In cell-based assays, Mark2 depletion indeed reduces Dvl gene expression and interrupts neural stem cell (NSCs) growth and differentiation, which are likely to be mediated through a decrease in class IIa HDAC phosphorylation and reduced H3K4ac and H3K27ac occupancies at the Dvl1/2 promoters. Finally, the detections of folate concentration in human brain tissue and NSCs and MEF cells indicates that folate deficiency contributes to the observed decreases in Mark2 and Dvl1 expression. Our present study raises a potential common pathogenicity mechanism in human lumbosacral spina bifida about DVL genes rather than their genetic pathogenic role.

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Acknowledgments

We appreciate help from Dr. Jonathan J. Wilde (Department of Pediatrics, University of Colorado Anschutz Medical Campus, Children’s Hospital Colorado) with the language editing. This study is supported by the National Natural Science Foundation of China, Beijing, China (No. 81471163; No. 81300489), National “973” project (2013CB945404), the National Science & Technology Pillar Program during the 12th Five-year Plan Period (2013BAI12B00).

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  1. Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Chaoyang District, Yabao Road 2, Beijing, 100020, China

    Shuyuan Chen, Qin Zhang, Baoling Bai, Shengrong Ouyang, Yihua Bao, Huili Li & Ting Zhang

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  1. Shuyuan Chen
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  2. Qin Zhang
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Shuyuan Chen and Qin Zhang equally contributed to this work.

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Chen, S., Zhang, Q., Bai, B. et al. MARK2/Par1b Insufficiency Attenuates DVL Gene Transcription via Histone Deacetylation in Lumbosacral Spina Bifida. Mol Neurobiol 54, 6304–6316 (2017). https://doi.org/10.1007/s12035-016-0164-0

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