Loss of histone methyltransferase ASH1L in the developing mouse brain causes autistic-like behaviors

AbstractAutism spectrum disorder (ASD) is a neurodevelopmental disease associated with various gene mutations. Recent genetic and clinical studies report that mutations of the epigenetic gene ASH1L are highly associated with human ASD and intellectual disability (ID). However, the causality and underlying molecular mechanisms linking ASH1L mutations to genesis of ASD/ID remain undetermined. Here we show loss of ASH1L in the developing mouse brain is sufficient to cause multiple developmental defects, core autistic-like behaviors, and impaired cognitive memory. Gene expression analyses uncover critical roles of ASH1L in regulating gene expression during neural cell development. Thus, our study establishes an ASD/ID mouse model revealing the critical function of an epigenetic factor ASH1L in normal brain development, a causality between Ash1L mutations and ASD/ID-like behaviors in mice, and potential molecular mechanisms linking Ash1L mutations to brain functional abnormalities.

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Loss of ASH1L in developing brains causes autistic-like behaviors in a mouse model

10.1101/2020.11.16.377259 ◽

2020 ◽

Author(s):

Yuen Gao ◽

Natalia Duque-Wilckens ◽

Mohammad B Aljazi ◽

Yan Wu ◽

Adam J Moeser ◽

...

Keyword(s):

Gene Expression ◽

Mouse Model ◽

Molecular Mechanisms ◽

Gene Mutations ◽

Causal Link ◽

Autism Spectrum ◽

Normal Brain ◽

Critical Function ◽

Developmental Defects ◽

Neurodevelopmental Disease

AbstractAutism spectrum disorder (ASD) is a neurodevelopmental disease associated with various gene mutations. Recent genetic and clinical studies report that mutations of the epigenetic gene ASH1L are highly associated with human ASD and intellectual disability (ID). However, the causal link between ASH1L mutations and ASD/ID remains undetermined. Here we show loss of ASH1L in developing mouse brains is sufficient to cause multiple developmental defects, core autistic-like behaviors, and impaired cognitive memory. Gene expression analyses uncover critical roles of ASH1L in regulating gene expression during neural cell development. Thus, our study establishes a new ASD/ID mouse model revealing the critical function of ASH1L in normal brain development, a causality between Ash1L mutations and ASD/ID-like behaviors in mice, and potential molecular mechanisms linking Ash1L mutations to brain functional abnormalities.

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Impaired KDM2B-mediated PRC1 recruitment to chromatin causes neural stem cell senescence and ASD/ID-like behavioral deficits

10.1101/2021.09.13.459918 ◽

2021 ◽

Author(s):

Yuen Gao ◽

Natalia Duque-Wilckens ◽

Mohammad B Aljazi ◽

Adam J Moeser ◽

George I Mias ◽

...

Keyword(s):

Molecular Mechanisms ◽

Critical Role ◽

Autism Spectrum ◽

Normal Brain ◽

Behavioral Deficits ◽

Adult Mice ◽

Cycle Arrest ◽

Developing Mouse Brain ◽

Underlying Mechanisms ◽

Polycomb Repressive Complex 1

AbstractAutism spectrum disorder (ASD) and intellectual disability (ID) are neurodevelopmental diseases associated with various genetic mutations. Recent clinical studies report that chromosomal 12q24.31 microdeletions are associated with human ASD/ID. However, the causality and underlying mechanisms linking 12q24.31 microdeletions to ASD/ID pathogenesis remain undetermined. Here we show Kdm2b, one of the genes located in chromosomal 12q24.31, plays a critical role in maintaining neural stem cells (NSCs) in the developing mouse brain. Loss of the CxxC-ZF domain of KDM2B impairs its function in recruiting Polycomb repressive complex 1 (PRC1) to chromatin, resulting in de-repression of genes involved in cell apoptosis, cell cycle arrest, NSC premature senescence, and leading to the loss of NSC populations in the brain. Importantly, the Kdm2b mutation is sufficient to induce ASD/ID-like social and memory deficits in adult mice. Thus, our study reveals a critical role of an epigenetic factor KDM2B in normal brain development, a causality between the Kdm2b mutation and genesis of ASD/ID-like phenotypes in mice, and potential molecular mechanisms linking the function of KDM2B-PRC1 in transcriptional regulation and NSC senescence to the12q24.31 microdeletion-associated ASD/ID.

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Specification of oxytocinergic and vasopressinergic circuits in the developing mouse brain

Communications Biology ◽

10.1038/s42003-021-02110-4 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

María del Pilar Madrigal ◽

Sandra Jurado

Keyword(s):

Autism Spectrum Disorder ◽

Mouse Brain ◽

Arginine Vasopressin ◽

3D Imaging ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Cellular Resolution ◽

Developing Mouse Brain ◽

Developmental Dynamics ◽

Appropriate Social Behaviors

AbstractOxytocin (OXT) and arginine vasopressin (AVP) support a broad range of behaviors and homeostatic functions including sex-specific and context-appropriate social behaviors. Although the alterations of these systems have been linked with social-related disorders such as autism spectrum disorder, their formation and developmental dynamics remain largely unknown. Using novel brain clearing techniques and 3D imaging, we have reconstructed the specification of oxytocinergic and vasopressinergic circuits in the developing mouse brain with unprecedented cellular resolution. A systematic quantification indicates that OXT and AVP neurons in the hypothalamus display distinctive developmental dynamics and high cellular plasticity from embryonic to early postnatal stages. Our findings reveal new insights into the specification and consolidation of neuropeptidergic systems in the developing CNS.

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Shank3 Modulates Sleep and Expression of Circadian Transcription Factors

10.1101/465799 ◽

2018 ◽

Author(s):

Ashley M. Ingiosi ◽

Taylor Wintler ◽

Hannah Schoch ◽

Kristan G. Singletary ◽

Dario Righelli ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factors ◽

Molecular Mechanisms ◽

Sleep Problems ◽

Wheel Running ◽

The United States ◽

Autism Spectrum ◽

Wheel Running Activity ◽

Falling Asleep ◽

Circadian Transcription

AbstractAutism Spectrum Disorder (ASD) is the most prevalent neurodevelopmental disorder in the United States and often co-presents with sleep problems. Sleep problems in ASD predict the severity of ASD core diagnostic symptoms and have a considerable impact on the quality of life of caregivers. Little is known, however, about the underlying molecular mechanisms. We investigated the role of Shank3, a high confidence ASD gene candidate, in sleep architecture and regulation. We show that mice lacking exon 21 of Shank3 have problems falling asleep even when sleepy. Using RNA-seq we show that sleep deprivation increases the differences in gene expression between mutants and wild types, downregulating circadian transcription factors Per3, Dec2, Hlf, Tef, and Reverbα. Shank3 mutants also have trouble regulating wheel-running activity in constant darkness. Overall our study shows that Shank3 is an important modulator of sleep and clock gene expression.

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Emx and Otx Gene Expression in the Developing Mouse Brain

Novartis Foundation Symposia - Ciba Foundation Symposium 193 - Development of the Cerebral Cortex ◽

10.1002/9780470514795.ch6 ◽

2007 ◽

pp. 100-126 ◽

Cited By ~ 2

Author(s):

Edoardo Boncinelli ◽

Massimo Gulisano ◽

Fabio Spada ◽

Vania Broccoli

Keyword(s):

Gene Expression ◽

Mouse Brain ◽

Developing Mouse Brain

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Identification of Hub Gene GRIN1 Correlated with Histological Grade and Prognosis of Glioma by Weighted Gene Coexpression Network Analysis

BioMed Research International ◽

10.1155/2021/4542995 ◽

2021 ◽

Vol 2021 ◽

pp. 1-22

Author(s):

Aoran Yang ◽

Xinhuan Wang ◽

Yaofeng Hu ◽

Chao Shang ◽

Yang Hong

Keyword(s):

Gene Expression ◽

Network Analysis ◽

Molecular Mechanisms ◽

The Cancer Genome Atlas ◽

Coexpression Network ◽

Normal Brain ◽

Gene Coexpression Network ◽

Gene Coexpression ◽

Coexpression Network Analysis ◽

Core Genes

The function of glutamate ionotropic receptor NMDA type subunit 1 (GRIN1) in neurodegenerative diseases has been widely reported; however, its role in the occurrence of glioma remains less explored. We obtained clinical data and transcriptome data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). Hub gene’s expression differential analysis and survival analysis were conducted by browsing the Gene Expression Profiling Interactive Analysis (GEPIA) database, Human Protein Atlas database, and LOGpc database. We conducted a variation analysis of datasets obtained from GEO and TCGA and performed a weighted gene coexpression network analysis (WGCNA) using the R programming language (3.6.3). Kaplan-Meier (KM) analysis was used to calculate the prognostic value of GRIN1. Finally, we conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Using STRING, we constructed a protein–protein interaction (PPI) network. Cytoscape software, a prerequisite of visualizing core genes, was installed, and CytoHubba detected the 10 most tumor-related core genes. We identified 185 differentially expressed genes (DEGs). GO and KEGG enrichment analyses illustrated that the identified DEGs are imperative in different biological functions and ascertained the potential pathways in which the DEGs may be enriched. The overall survival calculated by KM analysis showed that patients with lower expression of GRIN1 had worse prognoses than patients with higher expression of GRIN1 ( p = 0.004 ). The GEPIA and LOGpc databases were used to verify the expression difference of GRIN1 among GBM, LGG, and normal brain tissues. Ultimately, immunohistochemical assay results showed that GRIN1 was detected in normal tissue and not in the tumor specimens. Our results highlight a potential target for glioma treatment and will further our understanding of the molecular mechanisms underlying the treatment of glioma.

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Intracerebroventricular Infusion of Gangliosides Augments the Adult Neural Stem Cell Pool in Mouse Brain

ASN NEURO ◽

10.1177/1759091419884859 ◽

2019 ◽

Vol 11 ◽

pp. 175909141988485

Author(s):

Yutaka Itokazu ◽

Dongpei Li ◽

Robert K. Yu

Keyword(s):

Mouse Brain ◽

Expression Profiles ◽

Normal Brain ◽

Behavioral Deficits ◽

Adult Neural Stem Cell ◽

Intracerebroventricular Infusion ◽

5Xfad Mouse ◽

Developing Mouse Brain ◽

Ganglioside Gd3

We previously reported that ganglioside GD3 is the predominant species in neural stem cells (NSCs) and reduced postnatal NSC pools are observed in both the subventricular zone and dentate gyrus (DG) of GD3-synthase knockout (GD3S-KO) mouse brains. Specifically, deficiency of GD3 in GD3S-KO animals revealed a dramatic reduction in cellularity in the DG of the hippocampus of the developing mouse brain, resulting in severe behavioral deficits in these animals. To further evaluate the functional role of GD3 in postnatal brain, we performed rescue experiments by intracerebroventricular infusion of ganglioside GD3 in adult GD3S-KO animals and found that it could restore the NSC pools and enhance the NSCs for self-renewal. Furthermore, 5xFAD mouse model was utilized, and GD3 restored NSC numbers and GM1 promoted neuronal differentiation. Our results thus demonstrate that exogenously administered gangliosides are capable to restore the function of postnatal NSCs. Since ganglioside expression profiles are associated not only with normal brain development but also with pathogenic mechanisms of diseases, such as Alzheimer’s disease, we anticipate that the administration of exogenous gangliosides, such as GD3 and GM1, may represent a novel and effective strategy for promoting adult neurogenesis in damaged brain for disease treatment.

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High-resolution gene expression atlases for adult and developing mouse brain and spinal cord

Mammalian Genome ◽

10.1007/s00335-012-9406-2 ◽

2012 ◽

Vol 23 (9-10) ◽

pp. 539-549 ◽

Cited By ~ 36

Author(s):

Alex M. Henry ◽

John G. Hohmann

Keyword(s):

Gene Expression ◽

Spinal Cord ◽

High Resolution ◽

Mouse Brain ◽

Developing Mouse Brain ◽

Brain And Spinal Cord

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Assessing the requirements of prenatal UBE3A expression for rescue of behavioral phenotypes in a mouse model for Angelman syndrome

Molecular Autism ◽

10.1186/s13229-020-00376-9 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Monica Sonzogni ◽

Peipei Zhai ◽

Edwin J. Mientjes ◽

Geeske M. van Woerden ◽

Ype Elgersma

Keyword(s):

Gene Expression ◽

Mouse Model ◽

Brain Development ◽

Mouse Brain ◽

Angelman Syndrome ◽

Neurodevelopmental Disorder ◽

Brain Regions ◽

Critical Function ◽

Behavioral Phenotypes ◽

Mouse Brain Development

Abstract Background Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by the loss of functional ubiquitin protein ligase E3A (UBE3A). In neurons, UBE3A expression is tightly regulated by a mechanism of imprinting which suppresses the expression of the paternal UBE3A allele. Promising treatment strategies for AS are directed at activating paternal UBE3A gene expression. However, for such strategies to be successful, it is important to know when such a treatment should start, and how much UBE3A expression is needed for normal embryonic brain development. Methods Using a conditional mouse model of AS, we further delineated the critical period for UBE3A expression during early brain development. Ube3a gene expression was induced around the second week of gestation and mouse phenotypes were assessed using a behavioral test battery. To investigate the requirements of embryonic UBE3A expression, we made use of mice in which the paternal Ube3a allele was deleted. Results We observed a full behavioral rescue of the AS mouse model phenotypes when Ube3a gene reactivation was induced around the start of the last week of mouse embryonic development. We found that full silencing of the paternal Ube3a allele was not completed till the first week after birth but that deletion of the paternal Ube3a allele had no significant effect on the assessed phenotypes. Limitations Direct translation to human is limited, as we do not precisely know how human and mouse brain development aligns over gestational time. Moreover, many of the assessed phenotypes have limited translational value, as the underlying brain regions involved in these tasks are largely unknown. Conclusions Our findings provide further important insights in the requirement of UBE3A expression during brain development. We found that loss of up to 50% of UBE3A protein during prenatal mouse brain development does not significantly impact the assessed mouse behavioral phenotypes. Together with previous findings, our results indicate that the most critical function for mouse UBE3A lies in the early postnatal period between birth and P21.

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