A molecular model for neurodevelopmental disorders.

A B Diallo,G Maussion,V K Ota,K Vaillancourt,E S Chen,G G Chen,L Crapper,C Ernst,H Peng,J P Lopez,C Vasuta,C O Gigek

doi:10.1038/tp.2015.56

A B Diallo, G Maussion + Show 10 more

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https://doi.org/10.1038/tp.2015.56

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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.

Highlights

Neurodevelopmental disorders (NDDs) that affect behavior and cognition are caused by a wide variety of mutations, and several hypotheses have been put forward to understand the underlying features of the disease
We used short hairpin RNA stably incorporated into healthy neural stem cells to supress methyl-CpG binding domain 5 (MBD5) and special AT-rich binding protein 2 (SATB2) expression, and massively parallel RNA sequencing, DNA methylation sequencing and microRNA arrays to test the hypothesis that a primary etiology of neurodevelopmental disorder (NDD) is the disruption of the balance of NSC proliferation and differentiation
Discoveries in 2003 and 2004 led to a different theory about the underlying biology of NDDs, autistic disorders, based on the identification of mutations in NLGN3 and NLGN4.6 This paved the way for the synaptic hypothesis of NDDs,[7,8] which states that NDDs are caused by dysfunctional assembly or maintenance of synapses, a hypothesis which continues to be supported by the discovery of more mutations in non-NLGN genes involved in synapse formation or stability.[9,10]

Summary

Introduction

Neurodevelopmental disorders (NDDs) that affect behavior and cognition are caused by a wide variety of mutations, and several hypotheses have been put forward to understand the underlying features of the disease. The chromatin modification hypothesis[3] has continued to receive support, and mutations in other genes[4] related to genomic regulation have been identified in several cases.[5] Discoveries in 2003 and 2004 led to a different theory about the underlying biology of NDDs, autistic disorders, based on the identification of mutations in NLGN3 and NLGN4.6 This paved the way for the synaptic hypothesis of NDDs,[7,8] which states that NDDs are caused by dysfunctional assembly or maintenance of synapses, a hypothesis which continues to be supported by the discovery of more mutations in non-NLGN genes involved in synapse formation or stability.[9,10] Protein translation has been associated to NDDs,[11,12] and in conjunction with the chromatin modification hypothesis, suggests that regulation of major cell processes in neurons may predispose to NDDs. The degree to which these disparate hypotheses may be connected is not known, there is evidence to support WNT signaling as a potential convergence point.[13,14]

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