Centre d'Information et de documentation du CRA Rhône-Alpes
CRA
Informations pratiques
-
Adresse
Centre d'information et de documentation
du CRA Rhône-Alpes
Centre Hospitalier le Vinatier
bât 211
95, Bd Pinel
69678 Bron CedexHoraires
Lundi au Vendredi
9h00-12h00 13h30-16h00Contact
Tél: +33(0)4 37 91 54 65
Mail
Fax: +33(0)4 37 91 54 37
-
Détail de l'auteur
Auteur Xu ZHANG |
Documents disponibles écrits par cet auteur (2)
Faire une suggestion Affiner la recherche
The eIF4E homolog 4EHP (eIF4E2) regulates hippocampal long-term depression and impacts social behavior / Shane WIEBE in Molecular Autism, 11 (2020)
[article]
Titre : The eIF4E homolog 4EHP (eIF4E2) regulates hippocampal long-term depression and impacts social behavior Type de document : Texte imprimé et/ou numérique Auteurs : Shane WIEBE, Auteur ; Xiang Qi MENG, Auteur ; Sung-Hoon KIM, Auteur ; Xu ZHANG, Auteur ; Jean-Claude LACAILLE, Auteur ; Argel AGUILAR-VALLES, Auteur ; Nahum SONENBERG, Auteur Langues : Anglais (eng) Mots-clés : 4ehp Animal models Gigyf2 Long-term depression Social behavior Index. décimale : PER Périodiques Résumé : BACKGROUND: The regulation of protein synthesis is a critical step in gene expression, and its dysfunction is implicated in autism spectrum disorder (ASD). The eIF4E homologous protein (4EHP, also termed eIF4E2) binds to the mRNA 5' cap to repress translation. The stability of 4EHP is maintained through physical interaction with GRB10 interacting GYF protein 2 (GIGYF2). Gene-disruptive mutations in GIGYF2 are linked to ASD, but causality is lacking. We hypothesized that GIGYF2 mutations cause ASD by disrupting 4EHP function. METHODS: Since homozygous deletion of either gene is lethal, we generated a cell-type-specific knockout model where Eif4e2 (the gene encoding 4EHP) is deleted in excitatory neurons of the forebrain (4EHP-eKO). In this model, we investigated ASD-associated synaptic plasticity dysfunction, ASD-like behaviors, and global translational control. We also utilized mice lacking one copy of Gigyf2, Eif4e2 or co-deletion of one copy of each gene to further investigate ASD-like behaviors. RESULTS: 4EHP is expressed in excitatory neurons and synaptosomes, and its amount increases during development. 4EHP-eKO mice display exaggerated mGluR-LTD, a phenotype frequently observed in mouse models of ASD. Consistent with synaptic plasticity dysfunction, the mice displayed social behavior impairments without being confounded by deficits in olfaction, anxiety, locomotion, or motor ability. Repetitive behaviors and vocal communication were not affected by loss of 4EHP in excitatory neurons. Heterozygous deletion of either Gigyf2, Eif4e2, or both genes in mice did not result in ASD-like behaviors (i.e. decreases in social behavior or increases in marble burying). Interestingly, exaggerated mGluR-LTD and impaired social behaviors were not attributed to changes in hippocampal global protein synthesis, which suggests that 4EHP and GIGYF2 regulate the translation of specific mRNAs to mediate these effects. LIMITATIONS: This study did not identify which genes are translationally regulated by 4EHP and GIGYF2. Identification of mistranslated genes in 4EHP-eKO mice might provide a mechanistic explanation for the observed impairment in social behavior and exaggerated LTD. Future experiments employing affinity purification of translating ribosomes and mRNA sequencing in 4EHP-eKO mice will address this relevant issue. CONCLUSIONS: Together these results demonstrate an important role of 4EHP in regulating hippocampal plasticity and ASD-associated social behaviors, consistent with the link between mutations in GIGYF2 and ASD. En ligne : http://dx.doi.org/10.1186/s13229-020-00394-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=438
in Molecular Autism > 11 (2020)[article] The eIF4E homolog 4EHP (eIF4E2) regulates hippocampal long-term depression and impacts social behavior [Texte imprimé et/ou numérique] / Shane WIEBE, Auteur ; Xiang Qi MENG, Auteur ; Sung-Hoon KIM, Auteur ; Xu ZHANG, Auteur ; Jean-Claude LACAILLE, Auteur ; Argel AGUILAR-VALLES, Auteur ; Nahum SONENBERG, Auteur.
Langues : Anglais (eng)
in Molecular Autism > 11 (2020)
Mots-clés : 4ehp Animal models Gigyf2 Long-term depression Social behavior Index. décimale : PER Périodiques Résumé : BACKGROUND: The regulation of protein synthesis is a critical step in gene expression, and its dysfunction is implicated in autism spectrum disorder (ASD). The eIF4E homologous protein (4EHP, also termed eIF4E2) binds to the mRNA 5' cap to repress translation. The stability of 4EHP is maintained through physical interaction with GRB10 interacting GYF protein 2 (GIGYF2). Gene-disruptive mutations in GIGYF2 are linked to ASD, but causality is lacking. We hypothesized that GIGYF2 mutations cause ASD by disrupting 4EHP function. METHODS: Since homozygous deletion of either gene is lethal, we generated a cell-type-specific knockout model where Eif4e2 (the gene encoding 4EHP) is deleted in excitatory neurons of the forebrain (4EHP-eKO). In this model, we investigated ASD-associated synaptic plasticity dysfunction, ASD-like behaviors, and global translational control. We also utilized mice lacking one copy of Gigyf2, Eif4e2 or co-deletion of one copy of each gene to further investigate ASD-like behaviors. RESULTS: 4EHP is expressed in excitatory neurons and synaptosomes, and its amount increases during development. 4EHP-eKO mice display exaggerated mGluR-LTD, a phenotype frequently observed in mouse models of ASD. Consistent with synaptic plasticity dysfunction, the mice displayed social behavior impairments without being confounded by deficits in olfaction, anxiety, locomotion, or motor ability. Repetitive behaviors and vocal communication were not affected by loss of 4EHP in excitatory neurons. Heterozygous deletion of either Gigyf2, Eif4e2, or both genes in mice did not result in ASD-like behaviors (i.e. decreases in social behavior or increases in marble burying). Interestingly, exaggerated mGluR-LTD and impaired social behaviors were not attributed to changes in hippocampal global protein synthesis, which suggests that 4EHP and GIGYF2 regulate the translation of specific mRNAs to mediate these effects. LIMITATIONS: This study did not identify which genes are translationally regulated by 4EHP and GIGYF2. Identification of mistranslated genes in 4EHP-eKO mice might provide a mechanistic explanation for the observed impairment in social behavior and exaggerated LTD. Future experiments employing affinity purification of translating ribosomes and mRNA sequencing in 4EHP-eKO mice will address this relevant issue. CONCLUSIONS: Together these results demonstrate an important role of 4EHP in regulating hippocampal plasticity and ASD-associated social behaviors, consistent with the link between mutations in GIGYF2 and ASD. En ligne : http://dx.doi.org/10.1186/s13229-020-00394-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=438 Whole-genome sequencing in an autism multiplex family / Lingling SHI in Molecular Autism, (April 2013)
[article]
Titre : Whole-genome sequencing in an autism multiplex family Type de document : Texte imprimé et/ou numérique Auteurs : Lingling SHI, Auteur ; Xu ZHANG, Auteur ; Ryan GOLHAR, Auteur ; Frederick OTIENO, Auteur ; Mingze HE, Auteur ; Cuiping HOU, Auteur ; Cecilia KIM, Auteur ; Brendan KEATING, Auteur ; Gholson LYON, Auteur ; Kai WANG, Auteur ; Hakon HAKONARSON, Auteur Année de publication : 2013 Article en page(s) : 15 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : BACKGROUND:Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental disorders that affect 1 in 88 children in the US. Previous exome sequencing studies on family trios have implicated a role for rare, de-novo mutations in the pathogenesis of autism.METHODS:To examine the utility of whole-genome sequencing to identify inherited disease candidate variants and genes, we sequenced two probands from a large pedigree, including two parents and eight children. We evaluated multiple analytical strategies to identify a prioritized list of candidate genes.RESULTS:By assuming a recessive model of inheritance, we identified seven candidate genes shared by the two probands. We also evaluated a different analytical strategy that does not require the assumption of disease model, and identified a list of 59 candidate variants that may increase susceptibility to autism. Manual examination of this list identified ANK3 as the most likely candidate gene. Finally, we identified 33 prioritized non-coding variants such as those near SMG6 and COQ5, based on evolutionary constraint and experimental evidence from ENCODE. Although we were unable to confirm rigorously whether any of these genes indeed contribute to the disease, our analysis provides a prioritized shortlist for further validation studies.CONCLUSIONS:Our study represents one of the first whole-genome sequencing studies in autism leveraging a large family-based pedigree. These results provide for a discussion on the relative merits of finding de-novo mutations in sporadic cases versus finding inherited mutations in large pedigrees, in the context of neuropsychiatric and neurodevelopmental diseases. En ligne : http://dx.doi.org/10.1186/2040-2392-4-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=202
in Molecular Autism > (April 2013) . - 15 p.[article] Whole-genome sequencing in an autism multiplex family [Texte imprimé et/ou numérique] / Lingling SHI, Auteur ; Xu ZHANG, Auteur ; Ryan GOLHAR, Auteur ; Frederick OTIENO, Auteur ; Mingze HE, Auteur ; Cuiping HOU, Auteur ; Cecilia KIM, Auteur ; Brendan KEATING, Auteur ; Gholson LYON, Auteur ; Kai WANG, Auteur ; Hakon HAKONARSON, Auteur . - 2013 . - 15 p.
Langues : Anglais (eng)
in Molecular Autism > (April 2013) . - 15 p.
Index. décimale : PER Périodiques Résumé : BACKGROUND:Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental disorders that affect 1 in 88 children in the US. Previous exome sequencing studies on family trios have implicated a role for rare, de-novo mutations in the pathogenesis of autism.METHODS:To examine the utility of whole-genome sequencing to identify inherited disease candidate variants and genes, we sequenced two probands from a large pedigree, including two parents and eight children. We evaluated multiple analytical strategies to identify a prioritized list of candidate genes.RESULTS:By assuming a recessive model of inheritance, we identified seven candidate genes shared by the two probands. We also evaluated a different analytical strategy that does not require the assumption of disease model, and identified a list of 59 candidate variants that may increase susceptibility to autism. Manual examination of this list identified ANK3 as the most likely candidate gene. Finally, we identified 33 prioritized non-coding variants such as those near SMG6 and COQ5, based on evolutionary constraint and experimental evidence from ENCODE. Although we were unable to confirm rigorously whether any of these genes indeed contribute to the disease, our analysis provides a prioritized shortlist for further validation studies.CONCLUSIONS:Our study represents one of the first whole-genome sequencing studies in autism leveraging a large family-based pedigree. These results provide for a discussion on the relative merits of finding de-novo mutations in sporadic cases versus finding inherited mutations in large pedigrees, in the context of neuropsychiatric and neurodevelopmental diseases. En ligne : http://dx.doi.org/10.1186/2040-2392-4-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=202