Non-cell Autonomous OTX2 Homeoprotein Regulates Visual Cortex Plasticity Through Gadd45b/g

Apulei, Jessica; Kim, Namsuk; Testa, D.; Ribot, Jérôme; Morizet, David; Bernard, C.; Jourdren, Laurent; Blugeon, Corinne; Nardo, Ariel A. Di; Prochiantz, Alain

doi:10.1093/cercor/bhy108

Cited by 44 publications

(48 citation statements)

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“…Interestingly, we observe an effect despite a non-significant reduction in OTX2 accumulation in V-SVZ, which is likely due in part to the large distribution of mean OTX2 staining intensity. Small (~20%) decreases in OTX2 in adult mouse visual cortex induce cortical plasticity (Spatazza et al, 2013;, and OTX2 transcriptional targets can be activated at one concentration of OTX2 yet be suppressed at lower or higher concentrations (Apulei et al, 2018). Concentration-dependent targets of homeoprotein are shown to be dependent on chromatin state, whereby some targets are concentration insensitive while others are highly concentration-sensitive (Hannon et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

OTX2 signals from the choroid plexus to regulate adult neurogenesis

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et al. 2018

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Proliferation and migration during adult neurogenesis are regulated by a microenvironment originating from local vasculature, from cerebrospinal fluid produced by the choroid plexus, and from local supporting cells including astrocytes. Here, we focus on the function of Otx2 homeoprotein transcription factor in the adult subventricular zone which generates olfactory bulb neurons. We find that Otx2 secreted by choroid plexus is transferred to supporting cells of the subventricular zone and rostral migratory stream. Deletion of Otx2 in choroid plexus reduces the number of olfactory bulb newborn neurons and modifies extracellular matrix components produced by astrocytes. By expressing secreted single-chain antibodies to sequester Otx2 in the cerebrospinal fluid, we obtain similar results, demonstrating the importance of non-cell autonomous Otx2 in adult neurogenesis and suggesting a pivotal role for astrocytes. By using in vitro astrocytes co-cultured with neurospheres, we show that Otx2 down-regulates tenascin-C expression and subsequently modifies neuroblast migration. Thus, we reveal a multi-level and non-cell autonomous role of a homeoprotein, and reinforce the idea of the choroid plexus as a key niche compartment affecting adult neurogenesis.not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/243659 doi: bioRxiv preprint first posted online Jan. 5, 2018; 2 Introduction Neurogenesis in the adult mouse brain provides continuous replacement of interneurons in olfactory bulbs (OB) and is important for olfaction-based learning 1 . Neural stem cells, located in the adult subventricular zone (aSVZ) lining the lateral cerebral ventricles, give rise to progenitor cells (neuroblasts) that migrate though the rostral migratory stream (RMS) to reach the OB where they differentiate as interneurons and integrate into the network. The RMS is composed of a compacted neuroblast network forming chains that migrate along blood vessels and are surrounded by astrocytic processes 2,3 . While it is clear that RMS-associated astrocytes interact with neuroblasts 4 , the role of astrocytes for neuroblast migration is not well known. Astrocytes are also located in the aSVZ and are thought to play a role as supporting cells for regulating the neurogenic niche microenvironment 5 . The niche is further influenced by extrinsic factors coming from local vasculature and the cerebrospinal fluid (CSF) 6 . Furthermore, neural stem cells interact directly with both vasculature and CSF 7 . Indeed, it has been shown that molecules within the CSF can control aSVZ neurogenesis by regulating cell proliferation 8 or migration 9 . Homeoproteins are key regulators of neurogenesis both during embryogenesis and adult neurogenesis 10,11 . This class of transcription factors have the property to act both cellautonomously and non-cell-autonomously after secretion and internalization in target cells. The Otx2 homeoprotein is exp...

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Section: Discussionmentioning

confidence: 99%

OTX2 signals from the choroid plexus to regulate adult neurogenesis

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et al. 2018

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“…This homeoprotein is not produced anywhere in the cortex, but rather in sensory afferents and the choroid plexus (Spatazza et al 2013;Sugiyama et al 2008). Otx2 binds to PNNs and enters the future PV + cell, where it triggers a genetic program for critical period plasticity (Beurdeley et al 2012;Prochiantz and Di Nardo 2015;Testa et al 2019) by upregulation of Gadd45b, a DNA demethylase that orchestrates the large-scale change in the transcriptomic landscape during the critical period, including clustering of MeCP2 in the nucleus (Apulei et al 2019), where it has been shown to directly bind to and methylate the Pvalb promoter region (Patrizi et al 2019). Interestingly, MeCP2 has recently been shown to be a direct target of Ehmt1 in non-neuronal cells (Choi et al 2018).…”

Section: Discussionmentioning

confidence: 99%

EHMT1 regulates Parvalbumin-positive interneuron development and GABAergic input in sensory cortical areas

et al. 2020

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Mutations in the Euchromatic Histone Methyltransferase 1 (EHMT1) gene cause Kleefstra syndrome, a rare form of intellectual disability (ID) with strong autistic traits and sensory processing deficits. Proper development of inhibitory interneurons is crucial for sensory function. Here we report a timeline of Parvalbumin-positive (PV+) interneuron development in the three most important sensory cortical areas in the Ehmt1+/− mouse. We find a hitherto unreported delay of PV+ neuron maturation early in sensory development, with layer- and region-specific variability later in development. The delayed PV+ maturation is also reflected in a delayed maturation of GABAergic transmission in Ehmt1+/− auditory cortex, where we find a reduced GABA release probability specifically in putative PV+ synapses. Together with earlier reports of excitatory impairments in Ehmt1+/− neurons, we propose a shift in excitatory-inhibitory balance towards overexcitability in Ehmt1+/− sensory cortices as a consequence of early deficits in inhibitory maturation.

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“…One way to understand the molecular mechanism for juvenile plasticity is to investigate target genes regulated by a key transcription factor. The two studies on Otx2 reviewed here provided insights into the importance of physiological control such as channel function and stress regulation in PV cell development (Sakai et al., ), or of chromatin plasticity associated with DNA demethylation (Apulei et al., ). The other way of understanding the molecular mechanism for juvenile plasticity is to investigate critical‐period‐specific gene regulation from the epigenetic status of chromatin.…”

Section: Discussionmentioning

confidence: 99%

“…Factors regulating DNA methylation fluctuate during brain development, and expression of DNMT3a and Gadd45b/g peaks in the juvenile cortex (Apulei et al., ; Feng, Chang, Li, & Fan, ; Lister et al., ; Table ). Recently, Otx2 was demonstrated to directly regulate transcription of cortical Gadd45b/g (Apulei et al., ). Overexpression of Gadd45b induced de‐methylation of plastic gene loci such as c‐fos, and increased plasticity in the adult visual cortex.…”

Section: Experience‐dependent Regulation Of Dna Methylationmentioning

confidence: 99%

“…Overexpression of Gadd45b induced de‐methylation of plastic gene loci such as c‐fos, and increased plasticity in the adult visual cortex. Interestingly, nuclear foci of MeCP2, a methyl‐DNA binding factor, in PV cells returned to the juvenile pattern by reactivating the critical period via blockage of Otx2 in adults (Apulei et al., ). Thus, the experience‐mediator Otx2 not only induces a gene cascade for PV cell maturation and maintenance but also controls the regulator of chromatin state underlying plasticity.…”

Section: Experience‐dependent Regulation Of Dna Methylationmentioning

confidence: 99%

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Experience‐dependent transcriptional regulation in juvenile brain development

Sakai

Sugiyama

2018

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During brain development, once primary neural networks are formed, they are largely sculpted by environmental stimuli. The juvenile brain has a unique time window termed the critical period, in which neuronal circuits are remodeled by experience. Accumulating evidence indicates that abnormal rewiring of circuits in early life contributes to various neurodevelopmental disorders at later stages of life. Recent studies implicate two important aspects for activation of the critical period, both of which are experience‐dependent: (a) proper excitatory/inhibitory (E/I) balance of neural circuit achieved during developmental trajectory of inhibitory interneurons, and (b) epigenetic regulation allowing flexible gene expression for neuronal plasticity. In this review, we discuss the molecular mechanisms of juvenile brain plasticity from the viewpoints of transcriptional and chromatin regulation, with a focus on Otx2 homeoprotein. Depending on experience, Otx2 is transported into cortical parvalbumin‐positive interneurons (PV cells), where it induces PV cell maturation to activate the critical period. Understanding the unique behavior and function of Otx2 as a “messenger” of experience should therefore provide insights into mechanisms of juvenile brain development. Recently identified downstream targets of Otx2 suggest novel roles of Otx2 in homeostasis of PV cells, and, moreover, in regulation of chromatin state, which is important for neuronal plasticity. We further discuss epigenetic changes during postnatal brain development spanning the critical period. Different aspects of chromatin regulation may underlie experience‐dependent neuronal development and plasticity.

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Non-cell Autonomous OTX2 Homeoprotein Regulates Visual Cortex Plasticity Through Gadd45b/g

Cited by 44 publications

References 81 publications

OTX2 signals from the choroid plexus to regulate adult neurogenesis

OTX2 signals from the choroid plexus to regulate adult neurogenesis

EHMT1 regulates Parvalbumin-positive interneuron development and GABAergic input in sensory cortical areas

Experience‐dependent transcriptional regulation in juvenile brain development

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