title: A molecular model for neurodevelopmental disorders.
abstract: Genes implicated in neurodevelopmental disorders (NDDs) important in cognition and behavior may have convergent function and several cellular pathways have been implicated, including protein translational control, chromatin modification, and synapse assembly and maintenance. Here, we test the convergent effects of methyl-CpG binding domain 5 (MBD5) and special AT-rich binding protein 2 (SATB2) reduced dosage in human neural stem cells (NSCs), two genes implicated in 2q23.1 and 2q33.1 deletion syndromes, respectively, to develop a generalized model for NDDs. We used short hairpin RNA stably incorporated into healthy neural stem cells to supress MBD5 and SATB2 expression, and massively parallel RNA sequencing, DNA methylation sequencing and microRNA arrays to test the hypothesis that a primary etiology of NDDs is the disruption of the balance of NSC proliferation and differentiation. We show that reduced dosage of either gene leads to significant overlap of gene-expression patterns, microRNA patterns and DNA methylation states with control NSCs in a differentiating state, suggesting that a unifying feature of 2q23.1 and 2q33.1 deletion syndrome may be a lack of regulation between proliferation and differentiation in NSCs, as we observed previously for TCF4 and EHMT1 suppression following a similar experimental paradigm. We propose a model of NDDs whereby the balance of NSC proliferation and differentiation is affected, but where the molecules that drive this effect are largely specific to disease-causing genetic variation. NDDs are diverse, complex and unique, but the optimal balance of factors that determine when and where neural stem cells differentiate may be a major feature underlying the diverse phenotypic spectrum of NDDs.
authors.affiliation: Department of Psychiatry, McGill Group for Suicide Studies, McGill University, Montreal, QC, Canada.
authors.forename: C O
authors.initials: CO
authors.lastname: Gigek
authors.affiliation: Department of Psychiatry, McGill Group for Suicide Studies, McGill University, Montreal, QC, Canada.
authors.forename: E S
authors.initials: ES
authors.lastname: Chen
authors.affiliation: Department of Psychiatry, McGill Group for Suicide Studies, McGill University, Montreal, QC, Canada.
authors.forename: V K
authors.initials: VK
authors.lastname: Ota
authors.affiliation: Department of Psychiatry, McGill Group for Suicide Studies, McGill University, Montreal, QC, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Maussion
authors.affiliation: Department of Psychiatry, McGill Group for Suicide Studies, McGill University, Montreal, QC, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Peng
authors.affiliation: Department of Psychiatry, McGill Group for Suicide Studies, McGill University, Montreal, QC, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Vaillancourt
authors.affiliation: Department of Psychiatry, McGill Group for Suicide Studies, McGill University, Montreal, QC, Canada.
authors.forename: A B
authors.initials: AB
authors.lastname: Diallo
authors.affiliation: Department of Psychiatry, McGill Group for Suicide Studies, McGill University, Montreal, QC, Canada.
authors.forename: J P
authors.initials: JP
authors.lastname: Lopez
authors.affiliation: Department of Psychiatry, McGill Group for Suicide Studies, McGill University, Montreal, QC, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Crapper
authors.affiliation: Department of Psychiatry, McGill Group for Suicide Studies, McGill University, Montreal, QC, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Vasuta
authors.affiliation: Department of Psychiatry, McGill Group for Suicide Studies, McGill University, Montreal, QC, Canada.
authors.forename: G G
authors.initials: GG
authors.lastname: Chen
authors.affiliation: Department of Psychiatry, McGill Group for Suicide Studies, McGill University, Montreal, QC, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Ernst
mesh_terms: D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics*; D002478:Cells, Cultured; D002872:Chromosome Deletion; D002889:Chromosomes, Human, Pair 2; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics*; D044127:Epigenesis, Genetic; D018628:Gene Dosage; D018507:Gene Expression Regulation, Developmental; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D036961:Matrix Attachment Region Binding Proteins / Q000235:genetics*; D035683:MicroRNAs; D008958:Models, Molecular; D058953:Neural Stem Cells / Q000378:metabolism*; D065886:Neurodevelopmental Disorders / Q000235:genetics*; D055495:Neurogenesis / Q000235:genetics*; D017423:Sequence Analysis, RNA; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C550332:MBD5 protein, human; D036961:Matrix Attachment Region Binding Proteins; D035683:MicroRNAs; C521297:SATB2 protein, human; D014157:Transcription Factors