CHD7, the gene mutated in CHARGE syndrome, regulates genes involved in neural crest cell guidance
CHD7, the gene mutated in CHARGE syndrome, regulates genes involved in neural crest cell guidance
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DOI：
10.1007/s00439-014-1444-2
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发表时间：
2014-08-01
期刊：
影响因子：
5.3
通讯作者：
Pauli, Silke
中科院分区：
文献类型：
--
作者：
Schulz, Yvonne;Wehner, Peter;Pauli, Silke
CHD 7（染色体结构域解旋酶DNA结合蛋白7）中的杂合性功能缺失突变导致CHARGE综合征，这是一种影响颅面结构、颅神经和几个器官系统的复杂发育障碍。最近，研究表明，CHD 7对于多能迁移神经嵴细胞的形成至关重要，这些细胞从神经管迁移到胚胎的许多区域，在那里它们分化成各种组织，包括颅面和心脏结构。到目前为止，只有少数参与神经嵴细胞发育的CHD 7靶基因已被确定，并且CHD 7在神经嵴细胞引导和间充质-上皮转化的调节中的作用是未知的。因此，我们在第9.5天（神经嵴细胞迁移的时间点）对野生型和CHD 7缺陷（Chd 7（Whi/+）和Chd 7（Whi/Whi））小鼠胚胎进行了全基因组微阵列表达分析。我们确定了野生型和Chd 7（Whi/Whi）胚胎之间的98个差异表达基因。有趣的是，许多失调的基因参与神经嵴细胞和轴突导向，如信号蛋白和ephrin受体。通过在非洲爪蟾胚胎中进行Chd 7敲低实验，我们发现Sema 3a（一种参与卡尔曼综合征发病机制的蛋白质）在体内的表达模式异常。此外，我们在45名CHD 7阴性CHARGE患者中的3名中检测到非同义SEMA 3A变异。总之，我们首次发现Chd 7调节参与神经嵴细胞引导的基因，证明了CHARGE综合征发病机制的一个新方面。此外，我们显示了Sema 3a在不同物种中的保守调控机制，突出了其在发育过程中的重要性。虽然我们假设我们在CHD 7阴性CHARGE患者中发现的非同义SEMA 3A变体不足以产生表型，但我们认为SEMA 3A在这种多发畸形综合征的发病机制中起重要的修饰作用。
Heterozygous loss of function mutations in CHD7 (chromodomain helicase DNA-binding protein 7) lead to CHARGE syndrome, a complex developmental disorder affecting craniofacial structures, cranial nerves and several organ systems. Recently, it was demonstrated that CHD7 is essential for the formation of multipotent migratory neural crest cells, which migrate from the neural tube to many regions of the embryo, where they differentiate into various tissues including craniofacial and heart structures. So far, only few CHD7 target genes involved in neural crest cell development have been identified and the role of CHD7 in neural crest cell guidance and the regulation of mesenchymal-epithelial transition are unknown. Therefore, we undertook a genome-wide microarray expression analysis on wild-type and CHD7 deficient (Chd7 (Whi/+) and Chd7 (Whi/Whi) ) mouse embryos at day 9.5, a time point of neural crest cell migration. We identified 98 differentially expressed genes between wild-type and Chd7 (Whi/Whi) embryos. Interestingly, many misregulated genes are involved in neural crest cell and axon guidance such as semaphorins and ephrin receptors. By performing knockdown experiments for Chd7 in Xenopus laevis embryos, we found abnormalities in the expression pattern of Sema3a, a protein involved in the pathogenesis of Kallmann syndrome, in vivo. In addition, we detected non-synonymous SEMA3A variations in 3 out of 45 CHD7-negative CHARGE patients. In summary, we discovered for the first time that Chd7 regulates genes involved in neural crest cell guidance, demonstrating a new aspect in the pathogenesis of CHARGE syndrome. Furthermore, we showed for Sema3a a conserved regulatory mechanism across different species, highlighting its significance during development. Although we postulated that the non-synonymous SEMA3A variants which we found in CHD7-negative CHARGE patients alone are not sufficient to produce the phenotype, we suggest an important modifier role for SEMA3A in the pathogenesis of this multiple malformation syndrome.