Abnormal neocortex arealization and Sotos-like syndrome–associated behavior in
            <i>Setd2</i>
            mutant mice

Xu, Lichao; Zheng, Yue; Li, Xuejing; Wang, Yuzhuo; Huo, Dawei; Li, Qinglan; Wang, Shikang; Luo, Zhiyuan; Liu, Ying; Xu, Fuqiang; Wu, Xudong; Wu, Min; Zhou, Yan

doi:10.1126/sciadv.aba1180

Cited by 34 publications

(19 citation statements)

References 72 publications

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“…It is thus conceivable that FGF signaling and Nr2f1 might act together as upstream regulators of a cascade of molecular events governing area patterning, whereas other genes such as Pax6 and Emx2 would act either as secondary downstream effectors or in parallel pathways and have a weaker effect on arealization. Finally, several chromatin regulators, such as the methyl-transferase Setd2 (Xu et al, 2021 ), the transcription co-regulator Cited2 (Fame et al, 2016 ; Wagner and MacDonald, 2021 ) and the epigenetic co-factor LIM Domain Only-4 ( Lmo4 ; Harb et al, 2016 ), have been reported to influence area identity refinement. Considering Nr2f1 ability to recruit epigenetic factors (Montemayor et al, 2010 ), it might be interesting to investigate whether these or similar chromatin regulators act in association with or under the control of Nr2f1 in the late arealization process.…”

Section: Nr2f1 Specifies the Identity Of Posterior Sensory Areasmentioning

confidence: 99%

Structural and Functional Aspects of the Neurodevelopmental Gene NR2F1: From Animal Models to Human Pathology

Tocco

Bertacchi

Studer

2021

Front. Mol. Neurosci.

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The assembly and maturation of the mammalian brain result from an intricate cascade of highly coordinated developmental events, such as cell proliferation, migration, and differentiation. Any impairment of this delicate multi-factorial process can lead to complex neurodevelopmental diseases, sharing common pathogenic mechanisms and molecular pathways resulting in multiple clinical signs. A recently described monogenic neurodevelopmental syndrome named Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS) is caused by NR2F1 haploinsufficiency. The NR2F1 gene, coding for a transcriptional regulator belonging to the steroid/thyroid hormone receptor superfamily, is known to play key roles in several brain developmental processes, from proliferation and differentiation of neural progenitors to migration and identity acquisition of neocortical neurons. In a clinical context, the disruption of these cellular processes could underlie the pathogenesis of several symptoms affecting BBSOAS patients, such as intellectual disability, visual impairment, epilepsy, and autistic traits. In this review, we will introduce NR2F1 protein structure, molecular functioning, and expression profile in the developing mouse brain. Then, we will focus on Nr2f1 several functions during cortical development, from neocortical area and cell-type specification to maturation of network activity, hippocampal development governing learning behaviors, assembly of the visual system, and finally establishment of cortico-spinal descending tracts regulating motor execution. Whenever possible, we will link experimental findings in animal or cellular models to corresponding features of the human pathology. Finally, we will highlight some of the unresolved questions on the diverse functions played by Nr2f1 during brain development, in order to propose future research directions. All in all, we believe that understanding BBSOAS mechanisms will contribute to further unveiling pathophysiological mechanisms shared by several neurodevelopmental disorders and eventually lead to effective treatments.

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Section: Nr2f1 Specifies the Identity Of Posterior Sensory Areasmentioning

confidence: 99%

Structural and Functional Aspects of the Neurodevelopmental Gene NR2F1: From Animal Models to Human Pathology

Tocco

Bertacchi

Studer

2021

Front. Mol. Neurosci.

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“…However, only deficits in H2A.Z lead to dendritic arborization defects (Shen et al, 2018). Together deficits in NPC proliferation, neuronal differentiation, and arborization could contribute to the defects in arealization and the aberrant thalamo-cortical circuits associated with loss of Setd2 (Xu et al, 2021). Therefore, we posit that the modulation of the chromatin environment by SETD2 plays an important role in the regulation of cell fate transitions during neurogenesis, and the structural development of neuronal circuits.…”

Section: Setd2 Gain or Loss Of Function Differentially Impact Brain Sizementioning

confidence: 92%

“…Hence cell specific knockout studies will be important to define cell-type specific mechanisms governed by SETD2 during the development of neuronal circuitry. In fact, knockout of Setd2 in the developing forebrain revealed abnormal cortical arealization and aberrant thalamo-cortico-thalamic circuits in mice that also had defects in social interaction, motor learning and spatial memory (Xu et al, 2021). The observed neural phenotypes associated with SETD2 dysfunction could be related in part to changes in the chromatin environment.…”

Section: Setd2 Gain or Loss Of Function Differentially Impact Brain Sizementioning

confidence: 99%

“…In contrast to the Nsd1 mutant mice that does not show an enlarged head circumference, loss of function mutation in Apc2 resulted in a Sotos Syndrome-like phenotype in mice, with increased head circumference and dilated brain ventricles (Almuriekhi et al, 2015). Similar to NSD1, both SETD2 and SETD1A have also been implicated in the control of neuronal migration (Yu X. et al, 2019;Xu et al, 2021). However, divergent mechanisms could underlie a larger head size associated with loss of function mutations in SETD2 and SETD1A.…”

Section: Macrocephalymentioning

confidence: 99%

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The role of histone methyltransferases in neurocognitive disorders associated with brain size abnormalities

Ritchie

Lizarraga

2023

Front. Neurosci.

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Brain size is controlled by several factors during neuronal development, including neural progenitor proliferation, neuronal arborization, gliogenesis, cell death, and synaptogenesis. Multiple neurodevelopmental disorders have co-morbid brain size abnormalities, such as microcephaly and macrocephaly. Mutations in histone methyltransferases that modify histone H3 on Lysine 36 and Lysine 4 (H3K36 and H3K4) have been identified in neurodevelopmental disorders involving both microcephaly and macrocephaly. H3K36 and H3K4 methylation are both associated with transcriptional activation and are proposed to sterically hinder the repressive activity of the Polycomb Repressor Complex 2 (PRC2). During neuronal development, tri-methylation of H3K27 (H3K27me3) by PRC2 leads to genome wide transcriptional repression of genes that regulate cell fate transitions and neuronal arborization. Here we provide a review of neurodevelopmental processes and disorders associated with H3K36 and H3K4 histone methyltransferases, with emphasis on processes that contribute to brain size abnormalities. Additionally, we discuss how the counteracting activities of H3K36 and H3K4 modifying enzymes vs. PRC2 could contribute to brain size abnormalities which is an underexplored mechanism in relation to brain size control.

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“…All sections were counterstained with 4′,6‐diamidino‐2‐phenylindole dihydrochloride (DAPI, B2261; Sigma–Aldrich). The primary antibody used was rat anti‐BrdU (1:1000, ab6326; Abcam, Cambridge, UK) [Hewitt et al, 2021; Xu et al, 2021]. The fluorescent secondary antibody used was donkey anti‐rat Alexa Fluor 488 (1:500, A21208; Invitrogen, Carlsbad, CA) [Yang et al, 2016].…”

Section: Methodsmentioning

confidence: 99%

Hypomagnetic Field Exposure Affecting Gut Microbiota, Reactive Oxygen Species Levels, and Colonic Cell Proliferation in Mice

Zhan

Luo

Qin

et al. 2022

Bioelectromagnetics

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The gut microbiota has been considered one of the key factors in host health, which is influenced by many environmental factors. The geomagnetic field (GMF) represents one of the important environmental conditions for living organisms. Previous studies have shown that the elimination of GMF, the so-called hypomagnetic field (HMF), could affect the physiological functions and resistance to antibiotics of some microorganisms. However, whether long-term HMF exposure could alter the gut microbiota to some extent in mammals remains unclear. Here, we investigated the effects of long-term (8-and 12-week) HMF exposure on the gut microbiota in C57BL/6J mice. Our results clearly showed that 8-week HMF significantly affected the diversity and function of the mouse gut microbiota. Compared with the GMF group, the concentrations of short-chain fatty acids tended to decrease in the HMF group. Immunofluorescence analysis showed that HMF promoted colonic cell proliferation, concomitant with an increased level of reactive oxygen species (ROS). To our knowledge, this is the first in vivo finding that long-term HMF exposure could affect the mouse gut microbiota, ROS levels, and colonic cell proliferation in the colon. Moreover, the changes in gut microbiota can be restored by returning mice to the GMF environment, thus the possible harm to the microbiota caused by HMF exposure can be alleviated. Bioelectromagnetics. 43:462-475, 2022.

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Abnormal neocortex arealization and Sotos-like syndrome–associated behavior in Setd2 mutant mice

Cited by 34 publications

References 72 publications

Structural and Functional Aspects of the Neurodevelopmental Gene NR2F1: From Animal Models to Human Pathology

Structural and Functional Aspects of the Neurodevelopmental Gene NR2F1: From Animal Models to Human Pathology

The role of histone methyltransferases in neurocognitive disorders associated with brain size abnormalities

Hypomagnetic Field Exposure Affecting Gut Microbiota, Reactive Oxygen Species Levels, and Colonic Cell Proliferation in Mice

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