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.

Genetic contribution of retinoid-related genes to neural tube defects

“…As described in our previous article(Chen et al., ), we performed high‐throughput sequencing of genomic DNA samples collected from subjects with NTD in the Han Chinese population ranging in age from gestational week (GW) 12 to 10 years old and from multiple local hospitals in six provinces in China. Ethnicity‐matched controls were collected from non‐medically related terminations and were free of any NTDs.…”

“…Similar to our previous article (Chen et al., ), target sequencing was performed on CYP26B1 (NC_000002.11; NM_019885.3; NP_063938.1); CYP26A1 (NC_000010.10; NM_000783.3; NP_000774.2); CRABP1 (NC_000015.9; NM_004378.2; NP_004369.1); ALDH1A2 (NC_000015.9; NM_003888.3; NP_003879.2); CRABP2 (NC_000001.10; NM_001878.3; NP_001869.1); RARA (NC_000017.10; NM_000964.3; NP_000955.1). Genomic DNA was prepared using a Truseq DNA Sample preparation kit (Illumina Inc., San Diego, CA), libraries constructed with Agilent Custom SureSelect Enrichment Kit, and run on an Agilent Custom enrichment array (Probe Code: BI426526171).…”

Dishevelled Paralogs in Vertebrate Development: Redundant or Distinct?

“…Morphogenesis and closure of the neural tube is affected by nutritional, environmental and genetic factors including Wnt/PCP signaling, which is illustrated by genetic association between NTD in humans and mutations in the PCP genes VANGL1, VANGL2, CELSR1, FZD6 , and DVL2 (Cai and Shi, 2014; reviewed in De Marco et al, 2014). Notably, also mutations in DVL1 or DVL3 have been identified in humans with NTD (Figure 2), although the correlation was not significant (De Marco et al, 2013; Merello et al, 2013; Chen et al, 2016). …”

“…Mutations are indicated at the positions of amino acid changes. Changes detected in individuals with NTDs (De Marco et al, 2013; Merello et al, 2013; Chen et al, 2016) are color coded orange (predicted pathogenic) and gray (predicted benign, in all cases A>V). All ADRS mutations are (−1)-frameshift mutations resulting in altered amino acid sequences in the C-terminus and a premature stop (Bunn et al, 2015; White et al, 2015, 2016), which are indicated by hatched area and red line respectively.…”

Genetic screening and functional analysis of CASP9 mutations in a Chinese cohort with neural tube defects

“…The etiology of NTDs is complicated and involves both genetic and environmental factors. Epidemiological studies have revealed that folate deficiency may increase the risk of NTDs in humans, and that folic acid (FA) supplementation during periconception can reduce this risk . Although the genetic causation of human NTDs is poorly understood, studies in more than 240 mutant mouse models of NTDs provide the basis for a plausible pathological mechanism.…”