Arid1a regulates neural stem/progenitor cell proliferation and differentiation during cortical development

Liu, Xiao; Dai, Shang-Kun; Li, Peipei; Liu, Chang‐Mei

doi:10.1111/cpr.13124

Cited by 21 publications

(18 citation statements)

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“…Furthermore, early‐life inflammation and the potential roles for microglia have been documented in immune‐driven animal models of autism and schizophrenia 27 . These studies, together with our previous data showing that Arid1a has a high expression in microglia cells in CNS, 28 suggesting a potential role for Arid1a in microglia and inflammation phenotypes observed in neurodevelopmental disorders. However, there are no animal models available to study the direct role for Arid1a in the modulation of microglia phenotypes.…”

Section: Introductionsupporting

confidence: 61%

“…In the mouse CNS, Arid1a is highly expressed in astrocytes, neurons and microglia, 63 and lack of Arid1a in mouse NSPCs or human embryonic stem cells (hESCs) resulted in anomalous neurogenesis, accompanied by an increase of chromatin accessibility enrichment. 24 , 28 Our use of ATAC‐seq allowed us to connect microglia chromatin accessibility to the abnormal polarization pattern of M1/M2 microglia in Arid1a cKO mice. This connection, to our knowledge, has not been previously made.…”

Section: Discussionmentioning

confidence: 99%

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Abnormal microglial polarization induced by Arid1a deletion leads to neuronal differentiation deficits

et al. 2022

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Objective: Microglia, the prototypical innate immune cells of the central nervous system (CNS), are highly plastic and assume their phenotypes dependent on intrinsically genetic, epigenetic regulation or extrinsically microenvironmental cues. Microglia has been recognized as key regulators of neural stem/progenitor cells (NSPCs) and brain functions. Chromatin accessibility is implicated in immune cell development and functional regulation. However, it is still unknown whether and how chromatin remodelling regulates the phenotypic plasticity of microglia and exerts what kind of effects on NSPCs. Methods:We investigated the role of chromatin accessibility in microglia by deleting chromatin remodelling gene Arid1a using microglia-specific Cx3cr1-cre and Cx3cr1-CreERT2 mice. RNA-seq and ATAC-seq were performed to dissect the molecular mechanisms. In addition, we examined postnatal M1/M2 microglia polarization and analysed neuronal differentiation of NSPCs. Finally, we tested the effects of microglial Arid1a deletion on mouse behaviours.Results: Increased chromatin accessibility upon Arid1a ablation resulted in enhanced M1 microglial polarization and weakened M2 polarization, which led to abnormal neurogenesis and anxiety-like behaviours. Switching the polarization state under IL4 stimulation could rescue abnormal neurogenesis, supporting an essential role for chromatin remodeler ARID1A in balancing microglial polarization and brain functions.Conclusions: Our study identifies ARID1A as a central regulator of microglia polarization, establishing a mechanistic link between chromatin remodelling, neurogenesis and mouse behaviours, and highlights the potential development of innovative therapeutics exploiting the innate regenerative capacity of the nervous system. | INTRODUCTIONMicroglia, the only resident immune cells that enduringly reside in the central nervous system (CNS), 1 play vital roles in regulating the homeostasis of CNS. 2 In the past years, studies on microglia have expanded from investigating their immunological functions as resident macrophages of brain and mediators of neuroinflammation, injury, neurodegeneration to understanding their origins and functions involved in complex neurodevelopmental programs in the CNS. [3][4][5][6] Evidence has shown that microglia modulate neurogenesis and synaptic pruning, during which they interact with neural stem/progenitor cells (NSPCs) or neurons to provide trophic support, respond to

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Section: Introductionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Abnormal microglial polarization induced by Arid1a deletion leads to neuronal differentiation deficits

et al. 2022

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“…In the Barnes maze test, mice with acute knockdown of Arid1a in the hippocampi took a longer time to locate the target hole in the training trials (Fig EV1I ) and took a longer time to find the target hole (Fig EV1K ), while all mice displayed similar moving distances (Fig EV1J ). To further confirm the cognitive phenotype of Arid1a deficiency, we crossed Emx1 ‐ Cre mice with Arid1a fl / fl mice to produce Arid1a fl /+ ; Emx1 ‐ Cre mice (Liu et al , 2021 ) for behavioral assays. As we expected, the Arid1a fl /+ ; Emx1 ‐ Cre mice exhibited normal locomotive activities (Appendix Fig S1A and B) but severe cognitive impairment (Appendix Fig S1C–J).…”

Section: Resultsmentioning

confidence: 99%

Acetate supplementation restores cognitive deficits caused by ARID1A haploinsufficiency in excitatory neurons

et al. 2022

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Mutations in AT‐rich interactive domain‐containing protein 1A (ARID1A) cause Coffin‐Siris syndrome (CSS), a rare genetic disorder that results in mild to severe intellectual disabilities. However, the biological role of ARID1A in the brain remains unclear. In this study, we report that the haploinsufficiency of ARID1A in excitatory neurons causes cognitive impairment and defects in hippocampal synaptic transmission and dendritic morphology in mice. Similarly, human embryonic stem cell‐derived excitatory neurons with deleted ARID1A exhibit fewer dendritic branches and spines, and abnormal electrophysiological activity. Importantly, supplementation of acetate, an epigenetic metabolite, can ameliorate the morphological and electrophysiological deficits observed in mice with Arid1a haploinsufficiency, as well as in ARID1A‐null human excitatory neurons. Mechanistically, transcriptomic and ChIP‐seq analyses demonstrate that acetate supplementation can increase the levels of H3K27 acetylation at the promoters of key regulatory genes associated with neural development and synaptic transmission. Collectively, these findings support the essential roles of ARID1A in the excitatory neurons and cognition and suggest that acetate supplementation could be a potential therapeutic intervention for CSS.

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“…Several studies have addressed the role of Arid1a and Arid1b in the developing mouse brain. Cortex-specific homozygous deletion of Arid1a resulted in reduced cortical thickness linked to inhibition of IPC proliferation and decreased production of deep layer neurons ( Liu et al, 2021 ). In contrast, Arid1b deletion mainly affected ventral forebrain progenitors, suggesting differential requirement for Arid1a and Arid1b in distinct cellular compartments ( Moffat et al, 2021 ).…”

Section: Arid1a/arid1bmentioning

confidence: 99%

Transcription Pause and Escape in Neurodevelopmental Disorders

2022

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Transcription pause-release is an important, highly regulated step in the control of gene expression. Modulated by various factors, it enables signal integration and fine-tuning of transcriptional responses. Mutations in regulators of pause-release have been identified in a range of neurodevelopmental disorders that have several common features affecting multiple organ systems. This review summarizes current knowledge on this novel subclass of disorders, including an overview of clinical features, mechanistic details, and insight into the relevant neurodevelopmental processes.

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Arid1a regulates neural stem/progenitor cell proliferation and differentiation during cortical development

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 21 publications

References 37 publications

Abnormal microglial polarization induced by Arid1a deletion leads to neuronal differentiation deficits

Abnormal microglial polarization induced by Arid1a deletion leads to neuronal differentiation deficits

Acetate supplementation restores cognitive deficits caused by ARID1A haploinsufficiency in excitatory neurons

Transcription Pause and Escape in Neurodevelopmental Disorders

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