3 recherche sur le mot-clé 'Transcription factor'

Myt1l haploinsufficiency leads to obesity and multifaceted behavioral alterations in mice / Markus WÖHR in Molecular Autism, 13 (2022)  

Public ISBD [article]  inMolecular Autism > 13 (2022) . - 19 p. Titre : Myt1l haploinsufficiency leads to obesity and multifaceted behavioral alterations in mice Type de document : Texte imprimé et/ou numérique Auteurs : Markus WÖHR, Auteur ; Wendy M. FONG, Auteur ; Justyna A. JANAS, Auteur ; Moritz MALL, Auteur ; Christian THOME, Auteur ; Madhuri VANGIPURAM, Auteur ; Lingjun MENG, Auteur ; Thomas C. SÜDHOF, Auteur ; Marius WERNIG, Auteur Article en page(s) : 19 p. Langues : Anglais (eng) Mots-clés : Animals  Autism Spectrum Disorder/genetics  Behavior, Animal/physiology  Haploinsufficiency  Mice  Nerve Tissue Proteins/genetics  Obesity  Transcription Factors/genetics  Autism  Social behavior  Transcription factor  Ultrasonic vocalization Index. décimale : PER Périodiques Résumé : BACKGROUND: The zinc finger domain containing transcription factor Myt1l is tightly associated with neuronal identity and is the only transcription factor known that is both neuron-specific and expressed in all neuronal subtypes. We identified Myt1l as a powerful reprogramming factor that, in combination with the proneural bHLH factor Ascl1, could induce neuronal fate in fibroblasts. Molecularly, we found it to repress many non-neuronal gene programs, explaining its supportive role to induce and safeguard neuronal identity in combination with proneural bHLH transcriptional activators. Moreover, human genetics studies found MYT1L mutations to cause intellectual disability and autism spectrum disorder often coupled with obesity. METHODS: Here, we generated and characterized Myt1l-deficient mice. A comprehensive, longitudinal behavioral phenotyping approach was applied. RESULTS: Myt1l was necessary for survival beyond 24 h but not for overall histological brain organization. Myt1l heterozygous mice became increasingly overweight and exhibited multifaceted behavioral alterations. In mouse pups, Myt1l haploinsufficiency caused mild alterations in early socio-affective communication through ultrasonic vocalizations. In adulthood, Myt1l heterozygous mice displayed hyperactivity due to impaired habituation learning. Motor performance was reduced in Myt1l heterozygous mice despite intact motor learning, possibly due to muscular hypotonia. While anxiety-related behavior was reduced, acoustic startle reactivity was enhanced, in line with higher sensitivity to loud sound. Finally, Myt1l haploinsufficiency had a negative impact on contextual fear memory retrieval, while cued fear memory retrieval appeared to be intact. LIMITATIONS: In future studies, additional phenotypes might be identified and a detailed characterization of direct reciprocal social interaction behavior might help to reveal effects of Myt1l haploinsufficiency on social behavior in juvenile and adult mice. CONCLUSIONS: Behavioral alterations in Myt1l haploinsufficient mice recapitulate several clinical phenotypes observed in humans carrying heterozygous MYT1L mutations and thus serve as an informative model of the human MYT1L syndrome. En ligne : http://dx.doi.org/10.1186/s13229-022-00497-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=477 [article] Myt1l haploinsufficiency leads to obesity and multifaceted behavioral alterations in mice [Texte imprimé et/ou numérique] / Markus WÖHR, Auteur ; Wendy M. FONG, Auteur ; Justyna A. JANAS, Auteur ; Moritz MALL, Auteur ; Christian THOME, Auteur ; Madhuri VANGIPURAM, Auteur ; Lingjun MENG, Auteur ; Thomas C. SÜDHOF, Auteur ; Marius WERNIG, Auteur . - 19 p. Langues : Anglais (eng) in Molecular Autism > 13 (2022) . - 19 p. Mots-clés : Animals  Autism Spectrum Disorder/genetics  Behavior, Animal/physiology  Haploinsufficiency  Mice  Nerve Tissue Proteins/genetics  Obesity  Transcription Factors/genetics  Autism  Social behavior  Transcription factor  Ultrasonic vocalization Index. décimale : PER Périodiques Résumé : BACKGROUND: The zinc finger domain containing transcription factor Myt1l is tightly associated with neuronal identity and is the only transcription factor known that is both neuron-specific and expressed in all neuronal subtypes. We identified Myt1l as a powerful reprogramming factor that, in combination with the proneural bHLH factor Ascl1, could induce neuronal fate in fibroblasts. Molecularly, we found it to repress many non-neuronal gene programs, explaining its supportive role to induce and safeguard neuronal identity in combination with proneural bHLH transcriptional activators. Moreover, human genetics studies found MYT1L mutations to cause intellectual disability and autism spectrum disorder often coupled with obesity. METHODS: Here, we generated and characterized Myt1l-deficient mice. A comprehensive, longitudinal behavioral phenotyping approach was applied. RESULTS: Myt1l was necessary for survival beyond 24 h but not for overall histological brain organization. Myt1l heterozygous mice became increasingly overweight and exhibited multifaceted behavioral alterations. In mouse pups, Myt1l haploinsufficiency caused mild alterations in early socio-affective communication through ultrasonic vocalizations. In adulthood, Myt1l heterozygous mice displayed hyperactivity due to impaired habituation learning. Motor performance was reduced in Myt1l heterozygous mice despite intact motor learning, possibly due to muscular hypotonia. While anxiety-related behavior was reduced, acoustic startle reactivity was enhanced, in line with higher sensitivity to loud sound. Finally, Myt1l haploinsufficiency had a negative impact on contextual fear memory retrieval, while cued fear memory retrieval appeared to be intact. LIMITATIONS: In future studies, additional phenotypes might be identified and a detailed characterization of direct reciprocal social interaction behavior might help to reveal effects of Myt1l haploinsufficiency on social behavior in juvenile and adult mice. CONCLUSIONS: Behavioral alterations in Myt1l haploinsufficient mice recapitulate several clinical phenotypes observed in humans carrying heterozygous MYT1L mutations and thus serve as an informative model of the human MYT1L syndrome. En ligne : http://dx.doi.org/10.1186/s13229-022-00497-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=477

An investigation of NFXL1, a gene implicated in a study of specific language impairment / R. NUDEL in Journal of Neurodevelopmental Disorders, 8-1 (December 2016)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 8-1 (December 2016) . - p.13 Titre : An investigation of NFXL1, a gene implicated in a study of specific language impairment Type de document : Texte imprimé et/ou numérique Auteurs : R. NUDEL, Auteur Article en page(s) : p.13 Langues : Anglais (eng) Mots-clés : Cerebellum  Language disorder  Nfxl1  Neurodevelopment  Neurogenetics  Specific language impairment  Transcription factor Index. décimale : PER Périodiques Résumé : BACKGROUND: A recent study identified NFXL1 as a candidate gene for specific language impairment. The protein encoded by this gene is predicted to be a transcription factor based on domain similarities with NFX1, a repressor of HLA class II genes, which have themselves been implicated in specific language impairment. However, there is very little literature on the function of NFXL1. METHODS: This report describes a study of NFXL1 expression in several human tissues and an investigation of differential expression in several specific brain regions through quantitative PCR as well as a study of the protein's sub-cellular localization in HEK cells and SH-SY5Y cells through immunofluorescence. RESULTS: The NFXL1 transcript was found in all investigated tissues. In the brain, a high level of NFXL1 expression was found in the cerebellum. An analysis of the sub-cellular localization of the protein showed a cytoplasmic pattern in the investigated cells. CONCLUSIONS: The NFXL1 transcript was present in samples from different tissues; in the brain, a high expression level was found in a region implicated in some language-related pathologies. NFXL1 did not show nuclear localization, suggesting that, if it regulates transcription, certain conditions may be required for it to translocate to the nucleus. En ligne : http://dx.doi.org/10.1186/s11689-016-9146-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=348 [article] An investigation of NFXL1, a gene implicated in a study of specific language impairment [Texte imprimé et/ou numérique] / R. NUDEL, Auteur . - p.13. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 8-1 (December 2016) . - p.13 Mots-clés : Cerebellum  Language disorder  Nfxl1  Neurodevelopment  Neurogenetics  Specific language impairment  Transcription factor Index. décimale : PER Périodiques Résumé : BACKGROUND: A recent study identified NFXL1 as a candidate gene for specific language impairment. The protein encoded by this gene is predicted to be a transcription factor based on domain similarities with NFX1, a repressor of HLA class II genes, which have themselves been implicated in specific language impairment. However, there is very little literature on the function of NFXL1. METHODS: This report describes a study of NFXL1 expression in several human tissues and an investigation of differential expression in several specific brain regions through quantitative PCR as well as a study of the protein's sub-cellular localization in HEK cells and SH-SY5Y cells through immunofluorescence. RESULTS: The NFXL1 transcript was found in all investigated tissues. In the brain, a high level of NFXL1 expression was found in the cerebellum. An analysis of the sub-cellular localization of the protein showed a cytoplasmic pattern in the investigated cells. CONCLUSIONS: The NFXL1 transcript was present in samples from different tissues; in the brain, a high expression level was found in a region implicated in some language-related pathologies. NFXL1 did not show nuclear localization, suggesting that, if it regulates transcription, certain conditions may be required for it to translocate to the nucleus. En ligne : http://dx.doi.org/10.1186/s11689-016-9146-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=348

Functional characterization of rare FOXP2 variants in neurodevelopmental disorder / S. B. ESTRUCH in Journal of Neurodevelopmental Disorders, 8-1 (December 2016)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 8-1 (December 2016) . - p.44 Titre : Functional characterization of rare FOXP2 variants in neurodevelopmental disorder Type de document : Texte imprimé et/ou numérique Auteurs : S. B. ESTRUCH, Auteur ; S. A. GRAHAM, Auteur ; S. M. CHINNAPPA, Auteur ; P. DERIZIOTIS, Auteur ; S. E. FISHER, Auteur Article en page(s) : p.44 Langues : Anglais (eng) Mots-clés : Functional genetics  Language  Neuroscience  Speech  Transcription factor Index. décimale : PER Périodiques Résumé : BACKGROUND: Heterozygous disruption of FOXP2 causes a rare form of speech and language impairment. Screens of the FOXP2 sequence in individuals with speech/language-related disorders have identified several rare protein-altering variants, but their phenotypic relevance is often unclear. FOXP2 encodes a transcription factor with a forkhead box DNA-binding domain, but little is known about the functions of protein regions outside this domain. METHODS: We performed detailed functional analyses of seven rare FOXP2 variants found in affected cases, including three which have not been previously characterized, testing intracellular localization, transcriptional regulation, dimerization, and interaction with other proteins. To shed further light on molecular functions of FOXP2, we characterized the interaction between this transcription factor and co-repressor proteins of the C-terminal binding protein (CTBP) family. Finally, we analysed the functional significance of the polyglutamine tracts in FOXP2, since tract length variations have been reported in cases of neurodevelopmental disorder. RESULTS: We confirmed etiological roles of multiple FOXP2 variants. Of three variants that have been suggested to cause speech/language disorder, but never before been characterized, only one showed functional effects. For the other two, we found no effects on protein function in any assays, suggesting that they are incidental to the phenotype. We identified a CTBP-binding region within the N-terminal portion of FOXP2. This region includes two amino acid substitutions that occurred on the human lineage following the split from chimpanzees. However, we did not observe any effects of these amino acid changes on CTBP binding or other core aspects of FOXP2 function. Finally, we found that FOXP2 variants with reduced polyglutamine tracts did not exhibit altered behaviour in cellular assays, indicating that such tracts are non-essential for core aspects of FOXP2 function, and that tract variation is unlikely to be a highly penetrant cause of speech/language disorder. CONCLUSIONS: Our findings highlight the importance of functional characterization of novel rare variants in FOXP2 in assessing the contribution of such variants to speech/language disorder and provide further insights into the molecular function of the FOXP2 protein. En ligne : http://dx.doi.org/10.1186/s11689-016-9177-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=349 [article] Functional characterization of rare FOXP2 variants in neurodevelopmental disorder [Texte imprimé et/ou numérique] / S. B. ESTRUCH, Auteur ; S. A. GRAHAM, Auteur ; S. M. CHINNAPPA, Auteur ; P. DERIZIOTIS, Auteur ; S. E. FISHER, Auteur . - p.44. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 8-1 (December 2016) . - p.44 Mots-clés : Functional genetics  Language  Neuroscience  Speech  Transcription factor Index. décimale : PER Périodiques Résumé : BACKGROUND: Heterozygous disruption of FOXP2 causes a rare form of speech and language impairment. Screens of the FOXP2 sequence in individuals with speech/language-related disorders have identified several rare protein-altering variants, but their phenotypic relevance is often unclear. FOXP2 encodes a transcription factor with a forkhead box DNA-binding domain, but little is known about the functions of protein regions outside this domain. METHODS: We performed detailed functional analyses of seven rare FOXP2 variants found in affected cases, including three which have not been previously characterized, testing intracellular localization, transcriptional regulation, dimerization, and interaction with other proteins. To shed further light on molecular functions of FOXP2, we characterized the interaction between this transcription factor and co-repressor proteins of the C-terminal binding protein (CTBP) family. Finally, we analysed the functional significance of the polyglutamine tracts in FOXP2, since tract length variations have been reported in cases of neurodevelopmental disorder. RESULTS: We confirmed etiological roles of multiple FOXP2 variants. Of three variants that have been suggested to cause speech/language disorder, but never before been characterized, only one showed functional effects. For the other two, we found no effects on protein function in any assays, suggesting that they are incidental to the phenotype. We identified a CTBP-binding region within the N-terminal portion of FOXP2. This region includes two amino acid substitutions that occurred on the human lineage following the split from chimpanzees. However, we did not observe any effects of these amino acid changes on CTBP binding or other core aspects of FOXP2 function. Finally, we found that FOXP2 variants with reduced polyglutamine tracts did not exhibit altered behaviour in cellular assays, indicating that such tracts are non-essential for core aspects of FOXP2 function, and that tract variation is unlikely to be a highly penetrant cause of speech/language disorder. CONCLUSIONS: Our findings highlight the importance of functional characterization of novel rare variants in FOXP2 in assessing the contribution of such variants to speech/language disorder and provide further insights into the molecular function of the FOXP2 protein. En ligne : http://dx.doi.org/10.1186/s11689-016-9177-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=349