An early Sox2-dependent gene expression programme required for hippocampal dentate gyrus development

Mercurio, Sara; Alberti, Chiara; Serra, Linda; Meneghini, Simone; Berico, Pietro; Bertolini, Jessica; Becchetti, Andrea; Nicolis, Silvia K.

doi:10.1098/rsob.200339

Cited by 20 publications

(14 citation statements)

References 82 publications

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“…This is in agreement with a substantial conservation of overall neural cell proliferation during development reported in Fos-knock-out mice. 35 Whether Fos knockout in vivo would cause important defects in NSC survival/proliferation, pre-and postnatally, as observed in Sox2 mutants, 5,36 remains to be investigated.…”

Section: Fos Acts As a Mediator Of Sox2 Function In Nsc Self-renewal In Vitromentioning

confidence: 99%

Sox2 Controls Neural Stem Cell Self-Renewal Through a Fos-Centered Gene Regulatory Network

et al. 2021

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The Sox2 transcription factor is necessary for the long-term self-renewal of neural stem cells (NSCs). Its mechanism of action is still poorly defined. To identify molecules regulated by Sox2, and acting in mouse NSC maintenance, we transduced, into Sox2-deleted NSC, genes whose expression is strongly downregulated following Sox2 loss (Fos, Jun, Egr2), individually or in combination. Fos alone rescued long-term proliferation, as shown by in vitro cell growth and clonal analysis. Furthermore, pharmacological inhibition by T-5224 of FOS/JUN AP1 complex binding to its targets decreased cell proliferation and expression of the putative target Suppressor of cytokine signaling 3 (Socs3). Additionally, Fos requirement for efficient long-term proliferation was demonstrated by the reduction of NSC clones capable of long-term expansion following CRISPR/Cas9-mediated Fos inactivation. Previous work showed that the Socs3 gene is strongly downregulated following Sox2 deletion, and its re-expression by lentiviral transduction rescues long-term NSC proliferation. Fos appears to be an upstream regulator of Socs3, possibly together with Jun and Egr2; indeed, Sox2 re-expression in Sox2-deleted NSC progressively activates both Fos and Socs3 expression; in turn, Fos transduction activates Socs3 expression. Based on available SOX2 ChIPseq and ChIA-PET data, we propose a model whereby Sox2 is a direct activator of both Socs3 and Fos, as well as possibly Jun and Egr2; furthermore, we provide direct evidence for FOS and JUN binding on Socs3 promoter, suggesting direct transcriptional regulation. These results provide the basis for developing a model of a network of interactions, regulating critical effectors of NSC proliferation and long-term maintenance.

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Section: Fos Acts As a Mediator Of Sox2 Function In Nsc Self-renewal In Vitromentioning

confidence: 99%

Sox2 Controls Neural Stem Cell Self-Renewal Through a Fos-Centered Gene Regulatory Network

et al. 2021

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“…Upon Nr2f1 loss, the thalamic nuclei are affected in their size and connections, in turn impinging on the maturation of primary and secondary visual areas ( Figures 7D,E ; Zhou et al, 2001 ; Armentano et al, 2007 ; Chou et al, 2013 ). Interestingly, other key visual developmental factors, such as Sox2 , can converge to similar thalamic phenotypes, when lost or mutated, by affecting the size and connection of the dLGN in a similar way (Mercurio et al, 2021 ). This suggests that Nr2f1 might belong to a complex genetic network that is fundamental for the correct establishment of thalamic nuclei and their wiring to both cortex and retina.…”

Section: Nr2f1 Influences Complex Visual Associative Behaviors By Controlling Thalamic and Neocortical Developmentmentioning

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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“…Sox2 is one of the earliest neural markers and is essential for successful neurogenesis (Favaro et al, 2009; Mercurio et al, 2021). To describe the chromatin structure of the Sox2 locus in cells that adopt a neural fate we performed CHiC on tissues isolated from the heads of E11.5 embryos in which forebrain, midbrain, and hindbrain were pooled.…”

Section: Introductionmentioning

confidence: 99%

High affinity enhancer-promoter interactions can bypass CTCF/cohesin-mediated insulation and contribute to phenotypic robustness

Chakraborty

Kopitchinski

Eraso

et al. 2022

Preprint

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Transcriptional control by distal enhancers is an integral feature of gene regulation. To understand how enhancer-promoter interactions arise and assess the impact of disrupting 3D chromatin structure on gene expression, we generated an allelic series of mouse mutants that perturb the physical structure of the Sox2 locus. We show that in the epiblast and in neuronal tissues, CTCF-mediated loops are neither required for the interaction of the Sox2 promoter with distal enhancers, nor for its expression. Insertion of various combinations of CTCF motifs between Sox2 and its distal enhancers generated ectopic loops with varying degrees of insulation that directly correlated with reduced transcriptional output. Yet, even the mutants exhibiting the strongest insulation, with six CTCF motifs in divergent orientation, could not fully abolish activation by distal enhancers, and failed to disrupt implantation and neurogenesis. In contrast, cells of the anterior foregut were more susceptible to chromatin structure disruption with no detectable SOX2 expression in mutants with the strongest CTCF-mediated boundaries. These animals phenocopied loss of SOX2 in the anterior foregut, failed to separate trachea from esophagus and died perinatally. We propose that baseline transcription levels and enhancer density may influence the tissue-specific ability of distal enhancers to overcome physical barriers and maintain faithful gene expression. Our work suggests that high affinity enhancer-promoter interactions that can overcome chromosomal structural perturbations, play an essential role in maintaining phenotypic robustness.

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An early Sox2-dependent gene expression programme required for hippocampal dentate gyrus development

Cited by 20 publications

References 82 publications

Sox2 Controls Neural Stem Cell Self-Renewal Through a Fos-Centered Gene Regulatory Network

Sox2 Controls Neural Stem Cell Self-Renewal Through a Fos-Centered Gene Regulatory Network

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

High affinity enhancer-promoter interactions can bypass CTCF/cohesin-mediated insulation and contribute to phenotypic robustness

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