Altered Primary Somatosensory Neuron Development in a Pten Heterozygous Model for Autism Spectrum Disorder / Alejandra FERNANDEZ in Autism Research, 18-11 (November 2025)  

Public ISBD [article]  inAutism Research > 18-11 (November 2025) . - p.2192-2209 Titre : Altered Primary Somatosensory Neuron Development in a Pten Heterozygous Model for Autism Spectrum Disorder Type de document : texte imprimé Auteurs : Alejandra FERNANDEZ, Auteur ; Nick SARN, Auteur ; Charis ENG, Auteur ; Kevin M. WRIGHT, Auteur Article en page(s) : p.2192-2209 Langues : Anglais (eng) Mots-clés : autism Spectrum disorder  DRG  neuronal differentiation  PTEN  somatosensory Index. décimale : PER Périodiques Résumé : ABSTRACT Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by deficits in social interactions, repetitive behaviors, and hyper- or hyposensitivity to sensory stimuli. The cellular mechanisms underlying the emergence of abnormal sensory sensitivity in ASD are not fully understood. Recent studies in rodent models of ASD identified differences in dorsal root ganglia (DRG) neurons that convey somatosensory information to the central nervous system. However, it is unknown how ASD-associated alterations in DRG neurons emerge during development and if these phenotypes are conserved across ASD models. We examined Pten (phosphatase and tensin homolog) heterozygous mice (Pten Het ) as a model for syndromic ASD and identified altered responses to sensory stimuli. Transcriptomic and in vivo analysis identified alterations in subtype-specific markers of DRG neurons in Pten Het mice, emerging during early DRG development and involving dysregulation of signaling pathways downstream of PTEN. Finally, we show that mice harboring an ASD-associated mutation (Pten Y69H ) show nearly identical alterations in the expression of somatosensory neuron subtype-specific markers. These results show that precise levels of PTEN are required for proper somatosensory development and provide insight into the molecular and cellular basis of sensory abnormalities in a model for syndromic ASD. En ligne : https://doi.org/10.1002/aur.70119 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=571 [article] Altered Primary Somatosensory Neuron Development in a Pten Heterozygous Model for Autism Spectrum Disorder [texte imprimé] / Alejandra FERNANDEZ, Auteur ; Nick SARN, Auteur ; Charis ENG, Auteur ; Kevin M. WRIGHT, Auteur . - p.2192-2209. Langues : Anglais (eng) in Autism Research > 18-11 (November 2025) . - p.2192-2209 Mots-clés : autism Spectrum disorder  DRG  neuronal differentiation  PTEN  somatosensory Index. décimale : PER Périodiques Résumé : ABSTRACT Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by deficits in social interactions, repetitive behaviors, and hyper- or hyposensitivity to sensory stimuli. The cellular mechanisms underlying the emergence of abnormal sensory sensitivity in ASD are not fully understood. Recent studies in rodent models of ASD identified differences in dorsal root ganglia (DRG) neurons that convey somatosensory information to the central nervous system. However, it is unknown how ASD-associated alterations in DRG neurons emerge during development and if these phenotypes are conserved across ASD models. We examined Pten (phosphatase and tensin homolog) heterozygous mice (Pten Het ) as a model for syndromic ASD and identified altered responses to sensory stimuli. Transcriptomic and in vivo analysis identified alterations in subtype-specific markers of DRG neurons in Pten Het mice, emerging during early DRG development and involving dysregulation of signaling pathways downstream of PTEN. Finally, we show that mice harboring an ASD-associated mutation (Pten Y69H ) show nearly identical alterations in the expression of somatosensory neuron subtype-specific markers. These results show that precise levels of PTEN are required for proper somatosensory development and provide insight into the molecular and cellular basis of sensory abnormalities in a model for syndromic ASD. En ligne : https://doi.org/10.1002/aur.70119 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=571

Detailed phenotyping of Tbr1-2A-CreER knock-in mice demonstrates significant impacts on TBR1 protein levels and axon development / Grace K. O'BRIEN ; Kevin M. WRIGHT ; Brian J. O'ROAK in Autism Research, 18-5 (May 2025)  

Public ISBD [article]  inAutism Research > 18-5 (May 2025) . - p.922-932 Titre : Detailed phenotyping of Tbr1-2A-CreER knock-in mice demonstrates significant impacts on TBR1 protein levels and axon development Type de document : texte imprimé Auteurs : Grace K. O'BRIEN, Auteur ; Kevin M. WRIGHT, Auteur ; Brian J. O'ROAK, Auteur Article en page(s) : p.922-932 Langues : Anglais (eng) Mots-clés : anterior commissure  axon  cortex  mice  TBR1  transcription factor Index. décimale : PER Périodiques Résumé : Abstract Cre recombinase knock-in mouse lines have served as invaluable genetic tools for understanding key developmental processes altered in autism. However, insertion of exogenous DNA into the genome can have unintended effects on local gene regulation or protein function that must be carefully considered. Here, we analyze a recently generated Tbr1-2A-CreER knock-in mouse line, where a 2A-CreER cassette was inserted in-frame before the stop codon of the transcription factor gene Tbr1. Heterozygous TBR1 mutations in humans and mice are known to cause autism or autism-like behavioral phenotypes accompanied by structural brain malformations, most frequently a reduction of the anterior commissure (AC). Thus, it is critical for modified versions of Tbr1 to exhibit true wild-type-like activity. We evaluated the Tbr1-2A-CreER allele for its potential impact on Tbr1 function and complementation to Tbr1 loss-of-function alleles. In mice with one copy of the Tbr1-2A-CreER allele, we identified reduction of TBR1 protein in early postnatal cortex along with thinning of the AC, suggesting hypersensitivity of this structure to TBR1 dosage. Comparing Tbr1-2A-CreER and Tbr1-null mice to Tbr1-null complementation crosses showed reductions of TBR1 dosage ranging from 20% to 100%. Using six combinatorial genotypes, we found that moderate to severe TBR1 reductions ( 44%) were associated with cortical layer 5 expansion, while only the complete absence of TBR1 was associated with reeler-like ?inverted? cortical layering. In total, these results strongly support the conclusion that Tbr1-2A-CreER is a hypomorphic allele. We advise caution when interpreting experiments using this allele, considering the sensitivity of various corticogenic processes to TBR1 dosage and the association of heterozygous TBR1 mutations with complex neurodevelopmental disorders. En ligne : https://doi.org/10.1002/aur.3271 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=558 [article] Detailed phenotyping of Tbr1-2A-CreER knock-in mice demonstrates significant impacts on TBR1 protein levels and axon development [texte imprimé] / Grace K. O'BRIEN, Auteur ; Kevin M. WRIGHT, Auteur ; Brian J. O'ROAK, Auteur . - p.922-932. Langues : Anglais (eng) in Autism Research > 18-5 (May 2025) . - p.922-932 Mots-clés : anterior commissure  axon  cortex  mice  TBR1  transcription factor Index. décimale : PER Périodiques Résumé : Abstract Cre recombinase knock-in mouse lines have served as invaluable genetic tools for understanding key developmental processes altered in autism. However, insertion of exogenous DNA into the genome can have unintended effects on local gene regulation or protein function that must be carefully considered. Here, we analyze a recently generated Tbr1-2A-CreER knock-in mouse line, where a 2A-CreER cassette was inserted in-frame before the stop codon of the transcription factor gene Tbr1. Heterozygous TBR1 mutations in humans and mice are known to cause autism or autism-like behavioral phenotypes accompanied by structural brain malformations, most frequently a reduction of the anterior commissure (AC). Thus, it is critical for modified versions of Tbr1 to exhibit true wild-type-like activity. We evaluated the Tbr1-2A-CreER allele for its potential impact on Tbr1 function and complementation to Tbr1 loss-of-function alleles. In mice with one copy of the Tbr1-2A-CreER allele, we identified reduction of TBR1 protein in early postnatal cortex along with thinning of the AC, suggesting hypersensitivity of this structure to TBR1 dosage. Comparing Tbr1-2A-CreER and Tbr1-null mice to Tbr1-null complementation crosses showed reductions of TBR1 dosage ranging from 20% to 100%. Using six combinatorial genotypes, we found that moderate to severe TBR1 reductions ( 44%) were associated with cortical layer 5 expansion, while only the complete absence of TBR1 was associated with reeler-like ?inverted? cortical layering. In total, these results strongly support the conclusion that Tbr1-2A-CreER is a hypomorphic allele. We advise caution when interpreting experiments using this allele, considering the sensitivity of various corticogenic processes to TBR1 dosage and the association of heterozygous TBR1 mutations with complex neurodevelopmental disorders. En ligne : https://doi.org/10.1002/aur.3271 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=558

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