Partial loss of psychiatric risk gene Mir137 in mice causes repetitive behavior and impairs sociability and learning via increased Pde10a

Cheng, Ying; Wang, Zhimeng; Tan, Wui-Gee; Wang, Xiaona; Li, Yujing; Bai, Bing; Li, Yuxin; Zhang, Shuang-Feng; Yan, Hailiang; Chen, Zuo-Lun; Liu, Chang‐Mei; Mi, Ting-Wei; Xia, Shuting; Zhou, Zikai; Liu, An; Tang, Guping; Liu, Cong; Dai, Zhijie; Wang, Yingying; Wang, Hong; Wang, Xusheng; Kang, Yunhee; Lin, Li; Chen, Zhenping; Xie, Nina; Sun, Qing; Xie, Wei; Peng, Junmin; Chen, Dahua; Teng, Zhao‐Qian; Jin, Peng

doi:10.1038/s41593-018-0261-7

Cited by 120 publications

(141 citation statements)

References 77 publications

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“…Elucidating the specific cells and gene network regulated by each brain-expressed microRNAs is crucial for our understanding of both the mechanisms of neural circuit development and the etiology of neurodevelopmental disorders. A recent report demonstrated that in mouse partial loss of miR-137, a locus linked to autism and intellectual disability, impairs postnatal development and regulates synaptic plasticity by targeting the cyclic nucleotide phosphodiesterase family member Pde10a [35]. Here, we used mouse models with either constitutive inactivation or selectively hippocampal knockdown of the neurodevelopmental disease-associated gene Mir146a to evaluate the consequences of this inactivation on the differentiation and migration of neural stem cells, as well as on brain anatomy and cognition.…”

Section: Discussionmentioning

confidence: 99%

Loss of the neurodevelopmental disease-associated gene miR-146a impairs neural progenitor differentiation and causes learning and memory deficits

et al. 2020

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Background: Formation and maintenance of appropriate neural networks require tight regulation of neural stem cell proliferation, differentiation, and neurogenesis. microRNAs (miRNAs) play an important role in brain development and plasticity, and dysregulated miRNA profiles have been linked to neurodevelopmental disorders including autism, schizophrenia, or intellectual disability. Yet, the functional role of miRNAs in neural development and postnatal brain functions remains unclear. Methods: Using a combination of cell biology techniques as well as behavioral studies and brain imaging, we characterize mouse models with either constitutive inactivation or selectively hippocampal knockdown of the neurodevelopmental disease-associated gene Mir146a, the most commonly deregulated miRNA in developmental brain disorders (DBD). Results: We first show that during development, loss of miR-146a impairs the differentiation of radial glial cells, neurogenesis process, and neurite extension. In the mouse adult brain, loss of miR-146a correlates with an increased hippocampal asymmetry coupled with defects in spatial learning and memory performances. Moreover, selective hippocampal downregulation of miR-146a in adult mice causes severe hippocampal-dependent memory impairments indicating for the first time a role for this miRNA in postnatal brain functions. Conclusion: Our results show that miR-146a expression is critical for correct differentiation of neural stem cell during brain development and provide for the first time a strong argument for a postnatal role of miR-146a in regulating hippocampal-dependent memory. Furthermore, the demonstration that the Mir146a −/− mouse recapitulates several aspects reported in DBD patients, including impaired neurogenesis, abnormal brain anatomy, and working and spatial memories deficits, provides convincing evidence that the dysregulation of miR146a contributes to the pathogenesis of DBDs.

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Section: Discussionmentioning

confidence: 99%

Loss of the neurodevelopmental disease-associated gene miR-146a impairs neural progenitor differentiation and causes learning and memory deficits

et al. 2020

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“…PDE10A is mostly expressed in the retina (Wagner et al, 2013) and is involved in circadian rhythm, and the levels of the PDE10A protein display circadian rhythm at retinal photoreceptors (Wolloscheck et al, 2011), suggesting potential roles of this protein in the visual circle. PDE10A has gained attention as a therapeutic target for psychiatric disorders (Wilson and Brandon, 2015;Zhang et al, 2017;Cheng et al, 2018). Few studies have reported an association between PDE10A and myopia, and no prior study has analyzed the relationship between PDE10A and ocular parameters.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Association of Genetic Variants With Refraction, Axial Length, and Corneal Curvature: A Longitudinal Study of Chinese Schoolchildren

et al. 2020

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Background: Myopia is a common eye disorder that is approaching epidemic proportions worldwide. A genome-wide association study identified AREG (rs12511037), GABRR1 (rs13215566), and PDE10A (rs12206610) as being associated with refractive error in Asian populations. The present study investigated the associations between these three genetic variants and the occurrence and development of myopia, spherical equivalent refraction (SER), axial length (AL), and corneal curvature (CC) in a cohort of southeastern Chinese schoolchildren. Methods: We examined and followed 550 children in grade 1 enrolled in the Wenzhou Epidemiology of Refractive Error (WERE) project. During the 4-year follow-up, noncycloplegic refraction was evaluated twice each year, and the AL and CC were measured once every year. Age, sex, and the amounts of time spent on near work and outdoors were documented with a questionnaire. Sanger DNA sequencing was used to genotype single nucleotide polymorphisms (SNPs). SNPtest software was used to identify potential genetic variants associated with myopia, SER, AL, and CC. Ten thousand permutations were used to correct for multiple testing. Results: In total, 469 children, including 249 (53.1%) boys and 220 (46.9%) girls, were included in analyses. The mean age of all the children was 6.33 ± 0.48 years. After adjusting for age, sex, time spent on near work and time spent outdoors, neither the genotypes nor the allele frequencies of the three SNPs were significantly associated with myopic shift, incident myopia or the change in SER. After adjusting for age, sex, near-work time and outdoor time with 10,000 permutations, the genotype AREG (rs12511037) was associated with an increase in AL (P-values for the dominant, recessive, additive and general models were 0.0032, 0.0275, 0.0045, and 0.0099, respectively); the genotype PDE10A (rs12206610) was associated with a change in CC in the additive (P = 0.0096), dominant (P = 0.0096), and heterozygous models (P = 0.0096).

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“…In addition, common genetic variants within the gene that encodes miR-137 have been associated with ASD and schizophrenia 60,61 . In fact, the complete loss of miR-137 in mice is lethal, but a partial loss results in a phenotype which reproduces some of the core symptoms of ASD, such as repetitive behavior and impaired social functions 62 .…”

Section: Nfia (Nuclear Factor I A)mentioning

confidence: 99%

Postzygotic and germinalde novomutations in ASD: exploring their biological role

Gónzález

Cabanas

Amigo

et al. 2020

Preprint

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De novo mutations (DNMs), including germinal and postzygotic mutations (PZMs), are a strong source of causality for Autism Spectrum Disorder (ASD). However, the biological processes involved behind them remain unexplored. Our aim was to detect DNMs (germinal and PZMs) in a Spanish ASD cohort (360 trios) and to explore their role across different biological hierarchies (gene, biological pathway, cell and brain areas) using bioinformatic approaches. For the majority of the analysis, a combined cohort (N=2171 trios) with ASC (Autism Sequencing Consortium) previously published data was created. New plausible candidate genes for ASD such as FMR1 and NFIA were found. In addition, genes harboring PZMs were significantly enriched for miR-137 targets in comparison with germinal DNMs that were enriched in GO terms related to synaptic transmission. The expression pattern of genes with PZMs was restricted to early mid-fetal cortex. In contrast, the analysis of genes with germinal DNMs revealed a spatio-temporal window from early to mid-fetal development stages, with expression in the amygdala, cerebellum, cortex and striatum. These results provide evidence of the pathogenic role of PZMs and suggest the existence of distinct mechanisms between PZMs and germinal DNMs that are influencing ASD risk.

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Partial loss of psychiatric risk gene Mir137 in mice causes repetitive behavior and impairs sociability and learning via increased Pde10a

Cited by 120 publications

References 77 publications

Loss of the neurodevelopmental disease-associated gene miR-146a impairs neural progenitor differentiation and causes learning and memory deficits

Loss of the neurodevelopmental disease-associated gene miR-146a impairs neural progenitor differentiation and causes learning and memory deficits

Genome-Wide Association of Genetic Variants With Refraction, Axial Length, and Corneal Curvature: A Longitudinal Study of Chinese Schoolchildren

Postzygotic and germinalde novomutations in ASD: exploring their biological role

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