title: MARK2/Par1b Insufficiency Attenuates DVL Gene Transcription via Histone Deacetylation in Lumbosacral Spina Bifida.
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.
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Chaoyang District, Yabao Road 2, Beijing, 100020, China.
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Chen
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Chaoyang District, Yabao Road 2, Beijing, 100020, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Chaoyang District, Yabao Road 2, Beijing, 100020, China.
authors.forename: Baoling
authors.initials: B
authors.lastname: Bai
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Chaoyang District, Yabao Road 2, Beijing, 100020, China.
authors.forename: Shengrong
authors.initials: S
authors.lastname: Ouyang
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Chaoyang District, Yabao Road 2, Beijing, 100020, China.
authors.forename: Yihua
authors.initials: Y
authors.lastname: Bao
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Chaoyang District, Yabao Road 2, Beijing, 100020, China. lihuili2011@gmail.com.
authors.forename: Huili
authors.initials: H
authors.lastname: Li
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Chaoyang District, Yabao Road 2, Beijing, 100020, China. zhangtingcv2000@126.com.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
mesh_terms: D000107:Acetylation; D049109:Cell Proliferation / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D000072261:Dishevelled Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D058953:Neural Stem Cells / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D016135:Spinal Dysraphism / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C000606578:DVL1 protein, human; D000072261:Dishevelled Proteins; D006657:Histones; C094670:MARK2 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: DVL; Histone deacetylation; MARK2/Par1b; Neural tube defect; Rare variant; Wnt signaling