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Decreased nuclear Pten in neural stem cells contributes to deficits in neuronal maturation / Shin Chung KANG in Molecular Autism, 11 (2020)
[article]
Titre : Decreased nuclear Pten in neural stem cells contributes to deficits in neuronal maturation Type de document : Texte imprimé et/ou numérique Auteurs : Shin Chung KANG, Auteur ; Ritika JAINI, Auteur ; Masahiro HITOMI, Auteur ; Hyunpil LEE, Auteur ; Nick SARN, Auteur ; Stetson THACKER, Auteur ; Charis ENG, Auteur Article en page(s) : 43 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder Creb activation Neural development Neural stem cells Neuronal maturation PTEN mutation Index. décimale : PER Périodiques Résumé : BACKGROUND: PTEN, a syndromic autism spectrum disorder (ASD) risk gene, is mutated in approximately 10% of macrocephalic ASD cases. Despite the described genetic association between PTEN and ASD and ensuing studies, we continue to have a limited understanding of how PTEN disruption drives ASD pathogenesis and maintenance. METHODS: We derived neural stem cells (NSCs) from the dentate gyrus (DG) of Pten(m3m4) mice, a model that recapitulates PTEN-ASD phenotypes. We subsequently characterized the expression of stemness factors, proliferation, and differentiation of neurons and glia in Pten(m3m4) NSCs using immunofluorescent and immunoblotting approaches. We also measured Creb phosphorylation by Western blot analysis and expression of Creb-regulated genes with qRT-PCR. RESULTS: The m3m4 mutation decreases Pten localization to the nucleus and its global expression over time. Pten(m3m4) NSCs exhibit persistent stemness characteristics associated with increased proliferation and a resistance to neuronal maturation during differentiation. Given the increased proliferation of Pten(m3m4) NSCs, a significant increase in the population of immature neurons relative to mature neurons occurs, an approximately tenfold decrease in the ratio between the homozygous mutant and wildtype. There is an opposite pattern of differentiation in some Pten(m3m4) glia, specifically an increase in astrocytes. These aberrant differentiation patterns associate with changes in Creb activation in Pten(m3m4/m3m4) NSCs. We specifically observed loss of Creb phosphorylation at S133 in Pten(m3m4/m3m4) NSCs and a subsequent decrease in expression of Creb-regulated genes important to neuronal function (i.e., Bdnf). Interestingly, Bdnf treatment is able to partially rescue the stunted neuronal maturation phenotype in Pten(m3m4/m3m4) NSCs. CONCLUSIONS: Constitutional disruption of Pten nuclear localization with subsequent global decrease in Pten expression generates abnormal patterns of differentiation, a stunting of neuronal maturation. The propensity of Pten disruption to restrain neurons to a more progenitor-like state may be an important feature contributing to PTEN-ASD pathogenesis. En ligne : http://dx.doi.org/10.1186/s13229-020-00337-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427
in Molecular Autism > 11 (2020) . - 43 p.[article] Decreased nuclear Pten in neural stem cells contributes to deficits in neuronal maturation [Texte imprimé et/ou numérique] / Shin Chung KANG, Auteur ; Ritika JAINI, Auteur ; Masahiro HITOMI, Auteur ; Hyunpil LEE, Auteur ; Nick SARN, Auteur ; Stetson THACKER, Auteur ; Charis ENG, Auteur . - 43 p.
Langues : Anglais (eng)
in Molecular Autism > 11 (2020) . - 43 p.
Mots-clés : Autism spectrum disorder Creb activation Neural development Neural stem cells Neuronal maturation PTEN mutation Index. décimale : PER Périodiques Résumé : BACKGROUND: PTEN, a syndromic autism spectrum disorder (ASD) risk gene, is mutated in approximately 10% of macrocephalic ASD cases. Despite the described genetic association between PTEN and ASD and ensuing studies, we continue to have a limited understanding of how PTEN disruption drives ASD pathogenesis and maintenance. METHODS: We derived neural stem cells (NSCs) from the dentate gyrus (DG) of Pten(m3m4) mice, a model that recapitulates PTEN-ASD phenotypes. We subsequently characterized the expression of stemness factors, proliferation, and differentiation of neurons and glia in Pten(m3m4) NSCs using immunofluorescent and immunoblotting approaches. We also measured Creb phosphorylation by Western blot analysis and expression of Creb-regulated genes with qRT-PCR. RESULTS: The m3m4 mutation decreases Pten localization to the nucleus and its global expression over time. Pten(m3m4) NSCs exhibit persistent stemness characteristics associated with increased proliferation and a resistance to neuronal maturation during differentiation. Given the increased proliferation of Pten(m3m4) NSCs, a significant increase in the population of immature neurons relative to mature neurons occurs, an approximately tenfold decrease in the ratio between the homozygous mutant and wildtype. There is an opposite pattern of differentiation in some Pten(m3m4) glia, specifically an increase in astrocytes. These aberrant differentiation patterns associate with changes in Creb activation in Pten(m3m4/m3m4) NSCs. We specifically observed loss of Creb phosphorylation at S133 in Pten(m3m4/m3m4) NSCs and a subsequent decrease in expression of Creb-regulated genes important to neuronal function (i.e., Bdnf). Interestingly, Bdnf treatment is able to partially rescue the stunted neuronal maturation phenotype in Pten(m3m4/m3m4) NSCs. CONCLUSIONS: Constitutional disruption of Pten nuclear localization with subsequent global decrease in Pten expression generates abnormal patterns of differentiation, a stunting of neuronal maturation. The propensity of Pten disruption to restrain neurons to a more progenitor-like state may be an important feature contributing to PTEN-ASD pathogenesis. En ligne : http://dx.doi.org/10.1186/s13229-020-00337-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 Germline nuclear-predominant Pten murine model exhibits impaired social and perseverative behavior, microglial activation, and increased oxytocinergic activity / N. SARN in Molecular Autism, 12 (2021)
[article]
Titre : Germline nuclear-predominant Pten murine model exhibits impaired social and perseverative behavior, microglial activation, and increased oxytocinergic activity Type de document : Texte imprimé et/ou numérique Auteurs : N. SARN, Auteur ; S. THACKER, Auteur ; H. LEE, Auteur ; C. ENG, Auteur Article en page(s) : 41 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder Complement Microglia Mouse model Neurodegeneration Neuroinflammation Oxytocin PTEN mutation Social impairment Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) has a strong genetic etiology. Germline mutation in the tumor suppressor gene PTEN is one of the best described monogenic risk cases for ASD. Animal modeling of cell-specific Pten loss or mutation has provided insight into how disruptions to the function of PTEN affect neurodevelopment, neurobiology, and social behavior. As such, there is a growing need to understand more about how various aspects of PTEN activity and cell-compartment-specific functions, contribute to certain neurological or behavior phenotypes. METHODS: To understand more about the relationship between Pten localization and downstream effects on neurophenotypes, we generated the nuclear-predominant Pten(Y68H/+) mouse, which is identical to the genotype of some PTEN-ASD individuals. We subjected the Pten(Y68H/+) mouse to morphological and behavioral phenotyping, including the three-chamber sociability, open field, rotarod, and marble burying tests. We subsequently performed in vivo and in vitro cellular phenotyping and concluded the work with a transcriptomic survey of the Pten(Y68H/+) cortex, which profiled gene expression. RESULTS: We observe a significant increase in P-Akt downstream of canonical Pten signaling, macrocephaly, decreased sociability, decreased preference for novel social stimuli, increased repetitive behavior, and increased thigmotaxis in Pten(Y68H/+) six-week-old (P40) mice. In addition, we found significant microglial activation with increased expression of complement and neuroinflammatory proteins in vivo and in vitro accompanied by enhanced phagocytosis. These observations were subsequently validated with RNA-seq and qRT-PCR, which revealed overexpression of many genes involved in neuroinflammation and neuronal function, including oxytocin. Oxytocin transcript was fivefold overexpressed (P?=?0.0018), and oxytocin protein was strongly overexpressed in the Pten(Y68H/+) hypothalamus. CONCLUSIONS: The nuclear-predominant Pten(Y68H/+) model has clarified that Pten dysfunction links to microglial pathology and this associates with increased Akt signaling. We also demonstrate that Pten dysfunction associates with changes in the oxytocin system, an important connection between a prominent ASD risk gene and a potent neuroendocrine regulator of social behavior. These cellular and molecular pathologies may related to the observed changes in social behavior. Ultimately, the findings from this work may reveal important biomarkers and/or novel therapeutic modalities that could be explored in individuals with germline mutations in PTEN with ASD. En ligne : http://dx.doi.org/10.1186/s13229-021-00448-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459
in Molecular Autism > 12 (2021) . - 41 p.[article] Germline nuclear-predominant Pten murine model exhibits impaired social and perseverative behavior, microglial activation, and increased oxytocinergic activity [Texte imprimé et/ou numérique] / N. SARN, Auteur ; S. THACKER, Auteur ; H. LEE, Auteur ; C. ENG, Auteur . - 41 p.
Langues : Anglais (eng)
in Molecular Autism > 12 (2021) . - 41 p.
Mots-clés : Autism spectrum disorder Complement Microglia Mouse model Neurodegeneration Neuroinflammation Oxytocin PTEN mutation Social impairment Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) has a strong genetic etiology. Germline mutation in the tumor suppressor gene PTEN is one of the best described monogenic risk cases for ASD. Animal modeling of cell-specific Pten loss or mutation has provided insight into how disruptions to the function of PTEN affect neurodevelopment, neurobiology, and social behavior. As such, there is a growing need to understand more about how various aspects of PTEN activity and cell-compartment-specific functions, contribute to certain neurological or behavior phenotypes. METHODS: To understand more about the relationship between Pten localization and downstream effects on neurophenotypes, we generated the nuclear-predominant Pten(Y68H/+) mouse, which is identical to the genotype of some PTEN-ASD individuals. We subjected the Pten(Y68H/+) mouse to morphological and behavioral phenotyping, including the three-chamber sociability, open field, rotarod, and marble burying tests. We subsequently performed in vivo and in vitro cellular phenotyping and concluded the work with a transcriptomic survey of the Pten(Y68H/+) cortex, which profiled gene expression. RESULTS: We observe a significant increase in P-Akt downstream of canonical Pten signaling, macrocephaly, decreased sociability, decreased preference for novel social stimuli, increased repetitive behavior, and increased thigmotaxis in Pten(Y68H/+) six-week-old (P40) mice. In addition, we found significant microglial activation with increased expression of complement and neuroinflammatory proteins in vivo and in vitro accompanied by enhanced phagocytosis. These observations were subsequently validated with RNA-seq and qRT-PCR, which revealed overexpression of many genes involved in neuroinflammation and neuronal function, including oxytocin. Oxytocin transcript was fivefold overexpressed (P?=?0.0018), and oxytocin protein was strongly overexpressed in the Pten(Y68H/+) hypothalamus. CONCLUSIONS: The nuclear-predominant Pten(Y68H/+) model has clarified that Pten dysfunction links to microglial pathology and this associates with increased Akt signaling. We also demonstrate that Pten dysfunction associates with changes in the oxytocin system, an important connection between a prominent ASD risk gene and a potent neuroendocrine regulator of social behavior. These cellular and molecular pathologies may related to the observed changes in social behavior. Ultimately, the findings from this work may reveal important biomarkers and/or novel therapeutic modalities that could be explored in individuals with germline mutations in PTEN with ASD. En ligne : http://dx.doi.org/10.1186/s13229-021-00448-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459