title: CHD7, the gene mutated in CHARGE syndrome, regulates genes involved in neural crest cell guidance.
abstract: 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.
authors.affiliation: Institute of Human Genetics, University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37073, Göttingen, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Schulz
authors.forename: Peter
authors.initials: P
authors.lastname: Wehner
authors.forename: Lennart
authors.initials: L
authors.lastname: Opitz
authors.forename: Gabriela
authors.initials: G
authors.lastname: Salinas-Riester
authors.forename: Ernie M H F
authors.initials: EM
authors.lastname: Bongers
authors.forename: Conny M A
authors.initials: CM
authors.lastname: van Ravenswaaij-Arts
authors.forename: Josephine
authors.initials: J
authors.lastname: Wincent
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Schoumans
authors.forename: Jürgen
authors.initials: J
authors.lastname: Kohlhase
authors.forename: Annette
authors.initials: A
authors.lastname: Borchers
authors.forename: Silke
authors.initials: S
authors.lastname: Pauli
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D015153:Blotting, Western; D058747:CHARGE Syndrome / Q000235:genetics* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics*; D009432:Neural Crest; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014982:Xenopus laevis / Q000254:growth & development / Q000378:metabolism
chemical_list: D015415:Biomarkers; C507367:Chd7 protein, mouse; D004268:DNA-Binding Proteins; D012333:RNA, Messenger
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