Chd8 haploinsufficiency impairs early brain development and protein homeostasis later in life / Jessica A. JIMÉNEZ in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 74 p. Titre : Chd8 haploinsufficiency impairs early brain development and protein homeostasis later in life Type de document : texte imprimé Auteurs : Jessica A. JIMÉNEZ, Auteur ; Travis S. PTACEK, Auteur ; Alex H. TUTTLE, Auteur ; Ralf S. SCHMID, Auteur ; Sheryl S. MOY, Auteur ; Jeremy M. SIMON, Auteur ; Mark J. ZYLKA, Auteur Article en page(s) : 74 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Brain overgrowth  Chd8  Endoplasmic reticulum stress  Macrocephaly  Unfolded protein response Index. décimale : PER Périodiques Résumé : BACKGROUND: Chromodomain helicase DNA-binding protein 8 (Chd8) is a high-confidence risk gene for autism spectrum disorder (ASD). However, how Chd8 haploinsufficiency impairs gene expression in the brain and impacts behavior at different stages of life is unknown. METHODS: We generated a mutant mouse line with an ASD-linked loss-of-function mutation in Chd8 (V986*; stop codon mutation). We examined the behavior of Chd8 mutant mice along with transcriptional changes in the cerebral cortex as a function of age, with a focus on one embryonic (E14.5) and three postnatal ages (1, 6, and 12 months). RESULTS: Chd8(V986*/+) mutant mice displayed macrocephaly, reduced rearing responses and reduced center time in the open field, and enhanced social novelty preference. Behavioral phenotypes were more evident in Chd8(V986*/+) mutant mice at 1 year of age. Pup survival was reduced in wild-type x Chd8(V986*/+) crosses when the mutant parent was female. Transcriptomic analyses indicated that pathways associated with synaptic and neuronal projections and sodium channel activity were reduced in the cortex of embryonic Chd8(V986*/+) mice and then equalized relative to wild-type mice in the postnatal period. At 12 months of age, expression of genes associated with endoplasmic reticulum (ER) stress, chaperone-mediated protein folding, and the unfolded protein response (UPR) were reduced in Chd8(V986*/+) mice, whereas genes associated with the c-MET signaling pathway were increased in expression. LIMITATIONS: It is unclear whether the transcriptional changes observed with age in Chd8(V986*/+) mice reflect a direct effect of CHD8-regulated gene expression, or if CHD8 indirectly affects the expression of UPR/ER stress genes in adult mice as a consequence of neurodevelopmental abnormalities. CONCLUSIONS: Collectively, these data suggest that UPR/ER stress pathways are reduced in the cerebral cortex of aged Chd8(V986*/+) mice. Our study uncovers neurodevelopmental and age-related phenotypes in Chd8(V986*/+) mice and highlights the importance of controlling for age when studying Chd8 haploinsufficient mice. En ligne : http://dx.doi.org/10.1186/s13229-020-00369-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433 [article] Chd8 haploinsufficiency impairs early brain development and protein homeostasis later in life [texte imprimé] / Jessica A. JIMÉNEZ, Auteur ; Travis S. PTACEK, Auteur ; Alex H. TUTTLE, Auteur ; Ralf S. SCHMID, Auteur ; Sheryl S. MOY, Auteur ; Jeremy M. SIMON, Auteur ; Mark J. ZYLKA, Auteur . - 74 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 74 p. Mots-clés : Autism spectrum disorder  Brain overgrowth  Chd8  Endoplasmic reticulum stress  Macrocephaly  Unfolded protein response Index. décimale : PER Périodiques Résumé : BACKGROUND: Chromodomain helicase DNA-binding protein 8 (Chd8) is a high-confidence risk gene for autism spectrum disorder (ASD). However, how Chd8 haploinsufficiency impairs gene expression in the brain and impacts behavior at different stages of life is unknown. METHODS: We generated a mutant mouse line with an ASD-linked loss-of-function mutation in Chd8 (V986*; stop codon mutation). We examined the behavior of Chd8 mutant mice along with transcriptional changes in the cerebral cortex as a function of age, with a focus on one embryonic (E14.5) and three postnatal ages (1, 6, and 12 months). RESULTS: Chd8(V986*/+) mutant mice displayed macrocephaly, reduced rearing responses and reduced center time in the open field, and enhanced social novelty preference. Behavioral phenotypes were more evident in Chd8(V986*/+) mutant mice at 1 year of age. Pup survival was reduced in wild-type x Chd8(V986*/+) crosses when the mutant parent was female. Transcriptomic analyses indicated that pathways associated with synaptic and neuronal projections and sodium channel activity were reduced in the cortex of embryonic Chd8(V986*/+) mice and then equalized relative to wild-type mice in the postnatal period. At 12 months of age, expression of genes associated with endoplasmic reticulum (ER) stress, chaperone-mediated protein folding, and the unfolded protein response (UPR) were reduced in Chd8(V986*/+) mice, whereas genes associated with the c-MET signaling pathway were increased in expression. LIMITATIONS: It is unclear whether the transcriptional changes observed with age in Chd8(V986*/+) mice reflect a direct effect of CHD8-regulated gene expression, or if CHD8 indirectly affects the expression of UPR/ER stress genes in adult mice as a consequence of neurodevelopmental abnormalities. CONCLUSIONS: Collectively, these data suggest that UPR/ER stress pathways are reduced in the cerebral cortex of aged Chd8(V986*/+) mice. Our study uncovers neurodevelopmental and age-related phenotypes in Chd8(V986*/+) mice and highlights the importance of controlling for age when studying Chd8 haploinsufficient mice. En ligne : http://dx.doi.org/10.1186/s13229-020-00369-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433

Correction to: Chd8 haploinsufficiency impairs early brain development and protein homeostasis later in life / Jessica A. JIMÉNEZ in Molecular Autism, 12 (2021)  

Public ISBD [article]  inMolecular Autism > 12 (2021) . - 33 p. Titre : Correction to: Chd8 haploinsufficiency impairs early brain development and protein homeostasis later in life Type de document : texte imprimé Auteurs : Jessica A. JIMÉNEZ, Auteur ; Travis S. PTACEK, Auteur ; Alex H. TUTTLE, Auteur ; Ralf S. SCHMID, Auteur ; Sheryl S. MOY, Auteur ; Jeremy M. SIMON, Auteur ; Mark J. ZYLKA, Auteur Article en page(s) : 33 p. Langues : Anglais (eng) Index. décimale : PER Périodiques En ligne : http://dx.doi.org/10.1186/s13229-021-00438-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 [article] Correction to: Chd8 haploinsufficiency impairs early brain development and protein homeostasis later in life [texte imprimé] / Jessica A. JIMÉNEZ, Auteur ; Travis S. PTACEK, Auteur ; Alex H. TUTTLE, Auteur ; Ralf S. SCHMID, Auteur ; Sheryl S. MOY, Auteur ; Jeremy M. SIMON, Auteur ; Mark J. ZYLKA, Auteur . - 33 p. Langues : Anglais (eng) in Molecular Autism > 12 (2021) . - 33 p. Index. décimale : PER Périodiques En ligne : http://dx.doi.org/10.1186/s13229-021-00438-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459

A small-molecule screen reveals novel modulators of MeCP2 and X-chromosome inactivation maintenance / Hyeong-Min LEE in Journal of Neurodevelopmental Disorders, 12 (2020)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 12 (2020) Titre : A small-molecule screen reveals novel modulators of MeCP2 and X-chromosome inactivation maintenance Type de document : texte imprimé Auteurs : Hyeong-Min LEE, Auteur ; M Bram KUIJER, Auteur ; Nerea RUIZ BLANES, Auteur ; Ellen P. CLARK, Auteur ; Megumi AITA, Auteur ; Lorena GALIANO ARJONA, Auteur ; Agnieszka KOKOT, Auteur ; Noah SCIAKY, Auteur ; Jeremy M. SIMON, Auteur ; Sanchita BHATNAGAR, Auteur ; Benjamin D. PHILPOT, Auteur ; Andrea CERASE, Auteur Langues : Anglais (eng) Mots-clés : Animals  Chromosomes  Female  Male  Methyl-CpG-Binding Protein 2/genetics/metabolism  Mice  Mutation  Rett Syndrome/drug therapy/genetics  X Chromosome Inactivation  Ag490  Jak/stat  Janus Kinase  Janus Kinase inhibitors  MeCP2  PI3K/ATK pathways  Rett syndrome  X-chromosome inactivation Index. décimale : PER Périodiques Résumé : BACKGROUND: Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked methyl-CpG binding protein 2 (MeCP2) gene. While MeCP2 mutations are lethal in most males, females survive birth but show severe neurological defects. Because X-chromosome inactivation (XCI) is a random process, approximately 50% of the cells silence the wild-type (WT) copy of the MeCP2 gene. Thus, reactivating the silent WT copy of MeCP2 could provide therapeutic intervention for RTT. METHODS: Toward this goal, we screened ~ 28,000 small-molecule compounds from several libraries using a MeCP2-luciferase reporter cell line and cortical neurons from a MeCP2-EGFP mouse model. We used gain/increase of luminescence or fluorescence as a readout of MeCP2 reactivation and tested the efficacy of these drugs under different drug regimens, conditions, and cellular contexts. RESULTS: We identified inhibitors of the JAK/STAT pathway as XCI-reactivating agents, both by in vitro and ex vivo assays. In particular, we show that AG-490, a Janus Kinase 2 (JAK2) kinase inhibitor, and Jaki, a pan JAK/STAT inhibitor, are capable of reactivating MeCP2 from the inactive X chromosome, in different cellular contexts. CONCLUSIONS: Our results suggest that inhibition of the JAK/STAT pathway is a new potential pathway to reinstate MeCP2 gene expression as an efficient RTT treatment. En ligne : https://dx.doi.org/10.1186/s11689-020-09332-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573 [article] A small-molecule screen reveals novel modulators of MeCP2 and X-chromosome inactivation maintenance [texte imprimé] / Hyeong-Min LEE, Auteur ; M Bram KUIJER, Auteur ; Nerea RUIZ BLANES, Auteur ; Ellen P. CLARK, Auteur ; Megumi AITA, Auteur ; Lorena GALIANO ARJONA, Auteur ; Agnieszka KOKOT, Auteur ; Noah SCIAKY, Auteur ; Jeremy M. SIMON, Auteur ; Sanchita BHATNAGAR, Auteur ; Benjamin D. PHILPOT, Auteur ; Andrea CERASE, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 12 (2020) Mots-clés : Animals  Chromosomes  Female  Male  Methyl-CpG-Binding Protein 2/genetics/metabolism  Mice  Mutation  Rett Syndrome/drug therapy/genetics  X Chromosome Inactivation  Ag490  Jak/stat  Janus Kinase  Janus Kinase inhibitors  MeCP2  PI3K/ATK pathways  Rett syndrome  X-chromosome inactivation Index. décimale : PER Périodiques Résumé : BACKGROUND: Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked methyl-CpG binding protein 2 (MeCP2) gene. While MeCP2 mutations are lethal in most males, females survive birth but show severe neurological defects. Because X-chromosome inactivation (XCI) is a random process, approximately 50% of the cells silence the wild-type (WT) copy of the MeCP2 gene. Thus, reactivating the silent WT copy of MeCP2 could provide therapeutic intervention for RTT. METHODS: Toward this goal, we screened ~ 28,000 small-molecule compounds from several libraries using a MeCP2-luciferase reporter cell line and cortical neurons from a MeCP2-EGFP mouse model. We used gain/increase of luminescence or fluorescence as a readout of MeCP2 reactivation and tested the efficacy of these drugs under different drug regimens, conditions, and cellular contexts. RESULTS: We identified inhibitors of the JAK/STAT pathway as XCI-reactivating agents, both by in vitro and ex vivo assays. In particular, we show that AG-490, a Janus Kinase 2 (JAK2) kinase inhibitor, and Jaki, a pan JAK/STAT inhibitor, are capable of reactivating MeCP2 from the inactive X chromosome, in different cellular contexts. CONCLUSIONS: Our results suggest that inhibition of the JAK/STAT pathway is a new potential pathway to reinstate MeCP2 gene expression as an efficient RTT treatment. En ligne : https://dx.doi.org/10.1186/s11689-020-09332-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573

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