Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model

Stark, Kimberly L.; Xu, Bin; Bagchi, Anindya; Lai, Wen-Sung; Liu, Hui; Hsu, Ruby; Wan, Xiang; Pavlidis, Paul; Mills, Alea A.; Karayiorgou, Maria; Gogos, Joseph A.

doi:10.1038/ng.138

Cited by 556 publications

(714 citation statements)

References 49 publications

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“…3,4 Interestingly, principal effectors of RNAi -miRNA and siRNA -have been shown to have an essential role in the development and function of the central nervous system (CNS). 6,8,15 In addition, several authors have demonstrated relevant developmental brain defects in animal models deficient for AGO proteins 5,7 including a reduction in total number of neurons and glia. 5 On the basis of these findings, we speculate that haploinsufficiency of AGO genes at this locus has contributed to the neurocognitive deficits observed in our patients.…”

Section: Discussionmentioning

confidence: 99%

“…[5][6][7][8] In humans, the neuropsychiatric features seen in patients with 22q11.2 microdeletion syndrome are thought to result from haploinsufficiency of the DGCR8 gene and associated perturbations in miRNA biogenesis. 9 We present five patients with different but overlapping deletions involving the 1p34.3 locus, ranging in size from 1.1 to 3.1 Mb.…”

Section: Introductionmentioning

confidence: 99%

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Five children with deletions of 1p34.3 encompassing AGO1 and AGO3

et al. 2014

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Small RNAs (miRNA, siRNA, and piRNA) regulate gene expression through targeted destruction or translational repression of specific messenger RNA in a fundamental biological process called RNA interference (RNAi). The Argonaute proteins, which derive from a highly conserved family of genes found in almost all eukaryotes, are critical mediators of this process. Four AGO genes are present in humans, three of which (AGO 1, 3, and 4) reside in a cluster on chromosome 1p35p34. The effects of germline AGO variants or dosage alterations in humans are not known, however, prior studies have implicated dysregulation of the RNAi mechanism in the pathogenesis of several neurodevelopmental disorders. We describe five patients with hypotonia, poor feeding, and developmental delay who were found to have microdeletions of chromosomal region 1p34.3 encompassing the AGO1 and AGO3 genes. We postulate that haploinsufficiency of AGO1 and AGO3 leading to impaired RNAi may be responsible for the neurocognitive deficits present in these patients. However, additional studies with rigorous phenotypic characterization of larger cohorts of affected individuals and systematic investigation of the underlying molecular defects will be necessary to confirm this.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Five children with deletions of 1p34.3 encompassing AGO1 and AGO3

et al. 2014

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“…22q11DS mouse models present with a loss of glutamatergic synapses, decreased spine density, decreased CA1 pyramidal neuron complexity and reduced neurogenesis in the subventricular zone. The same mice show behavioural abnormalities in PPI, hyperlocomotion, fear conditioning and working memory [89][90][91][92][93][94] . 22q11DS is the only confirmed recurrent structural mutation associated with schizophrenia identified to date 95 .…”

Section: Q11mentioning

confidence: 99%

Estudos traducionais de neuropsiquiatria e esquizofrenia: modelos animais genéticos e de neurodesenvolvimento

Gottschalk

Sarnyai

Guest

et al. 2012

Arch. Clin. Psychiatry (São Paulo)

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Psychiatric symptoms are subjective by nature and tend to overlap between different disorders. The modelling of a neuropsychiatric disorder therefore faces challenges because of missing knowledge of the fundamental pathophysiology and a lack of accurate diagnostics. Animal models are used to test hypotheses of aetiology and to represent the human condition as close as possible to increase our understanding of the disease and to evaluate new targets for drug discovery. In this review, genetic and neurodevelopmental animal models of schizophrenia are discussed with respect to behavioural and neurophysiological findings and their association with the clinical condition. Only specific animal models of schizophrenia may ultimately lead to novel diagnostic approaches and drug discovery. We argue that molecular biomarkers are important to improve animal to human translation since behavioural readouts lack the necessary specificity and reliability to assess human psychiatric symptoms.Gottschalk MG, et al. / Rev Psiq Clín. 2013;40(1):41-50 Keywords: Translational research, neuropsychiatry, genetic, neurodevelopment, animal model, schizophrenia. ResumoSintomas psiquiátricos são subjetivos por natureza e tendem a se sobrepor entre diferentes desordens. Sendo assim, a criação de modelos de uma desordem neuropsiquiátrica encontra desafios pela falta de conhecimento dos fundamentos da fisiopatologia e diagnósticos precisos. Modelos animais são usados para testar hipóteses de etiologia e para representar a condição humana tão próximo quanto possível para aumentar nosso entendimento da doença e avaliar novos alvos para a descoberta de drogas. Nesta revisão, modelos animais genéticos e de neurodesenvolvimento de esquizofrenia são discutidos com respeito a achados comportamentais e neurofisiológicos e sua associação com a condição clínica. Somente modelos animais específicos de esquizofrenia podem, em último caso, levar a novas abordagens diagnósticas e descoberta de drogas. Argumentamos que biomarcadores moleculares são importantes para aumentar a tradução de animais a humanos, já que faltam a especificidade e a fidelidade necessárias às leituras comportamentais para avaliar sintomas psiquiátricos humanos.Gottschalk MG, et al. / Rev Psiq Clín. 2013;40(1):41-50

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“…22 Haploinsufficiency of DGCR8 in mice causes abnormal miRNA processing and induces behavioral and neuronal deficits similar to a subset of symptoms observed in DiGeorge syndrome. 23 The C-terminal portion of the 773-residue DGCR8 protein (residues 499-751) contains two double-stranded RNA-binding domains (dsRBDs) and a conserved C-terminal tail (CTT) that are sufficient for pri-miRNA processing. 18,24 The N-terminal portion of DGCR8 (residues 1-275) is required for nuclear localization.…”

mentioning

confidence: 99%

Structure of the dimerization domain of DiGeorge Critical Region 8

et al. 2010

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Maturation of microRNAs (miRNAs,~22nt) from long primary transcripts [primary miRNAs (pri-miRNAs)] is regulated during development and is altered in diseases such as cancer. The first processing step is a cleavage mediated by the Microprocessor complex containing the Drosha nuclease and the RNA-binding protein DiGeorge critical region 8 (DGCR8). We previously reported that dimeric DGCR8 binds heme and that the heme-bound DGCR8 is more active than the heme-free form. Here, we identified a conserved dimerization domain in DGCR8. Our crystal structure of this domain (residues 298-352) at 1.7 Å resolution demonstrates a previously unknown use of a WW motif as a platform for extensive dimerization interactions. The dimerization domain of DGCR8 is embedded in an independently folded heme-binding domain and directly contributes to association with heme. Heme-binding-deficient DGCR8 mutants have reduced pri-miRNA processing activity in vitro. Our study provides structural and biochemical bases for understanding how dimerization and heme binding of DGCR8 may contribute to regulation of miRNA biogenesis.

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Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model

Cited by 556 publications

References 49 publications

Five children with deletions of 1p34.3 encompassing AGO1 and AGO3

Five children with deletions of 1p34.3 encompassing AGO1 and AGO3

Estudos traducionais de neuropsiquiatria e esquizofrenia: modelos animais genéticos e de neurodesenvolvimento

Structure of the dimerization domain of DiGeorge Critical Region 8

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