A myelin-related transcriptomic profile is shared by Pitt–Hopkins syndrome models and human autism spectrum disorder

Phan, Ba Doi N.; Bohlen, Joseph F.; Davis, Brittany A.; Ye, Zengyou; Chen, Huei Ying; Mayfield, Brent; Sripathy, Srinidhi Rao; Page, Stephanie Cerceo; Campbell, Morganne N.; Smith, Hannah; Gallop, Danisha; Kim, Hyojin; Thaxton, Courtney; Simon, Jeremy M.; Burke, Emily E.; Shin, Joo Heon; Kennedy, Andrew; Sweatt, J. David; Philpot, Benjamin D.; Jaffe, Andrew E.; Maher, Brady J.

doi:10.1038/s41593-019-0578-x

Cited by 116 publications

(147 citation statements)

References 71 publications

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“…Thus, these data suggest that the deletion of Zbtb16 results in abnormal oligodendrogenesis, and eventually causes behavioral abnormalities such as ASD-and SCZ-like phenotypes. A recent study examined the role of the ASD-relevant gene TCF4 and found that Tcf4 mutant mice show impairments of oligodendrocyte development and myelination, supporting the significance of oligodendrocytes implicating ASD etiology 75 . In addition, reductions in white matter or corpus callosum volumes in the brains of ASD 76,77 and SCZ 78,79 subjects using diffusion tensor imaging (DTI) have been reported.…”

Section: Discussionmentioning

confidence: 92%

Zbtb16regulates social cognitive behaviors and neocortical development

Usui

Berto

Konishi

et al. 2020

Preprint

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Recent genetic studies have underscored the pleiotropic effects of single genes to multiple cognitive disorders. Mutations of ZBTB16 are associated with autism spectrum disorder (ASD) and schizophrenia (SCZ), but how the function of ZBTB16 is related to ASD or SCZ remains unknown. Here we show the deletion of Zbtb16 in mice leads to both ASD- and SCZ-like behaviors such as social impairment, repetitive behaviors, risk-taking behaviors, and cognitive impairment. To elucidate the mechanism underlying the behavioral phenotypes, we carried out histological studies and observed impairments in thinning of neocortical layer 6 (L6) and a reduction of TBR1+ neurons in the prefrontal cortex (PFC) of Zbtb16 KO mice. Furthermore, we found increased dendritic spines and microglia as well as developmental defects in oligodendrocytes and neocortical myelination in the PFC of Zbtb16 KO mice. Using a genomics approach, we identified the Zbtb16-transcriptome that includes genes involved in both ASD and SCZ pathophysiology and neocortical maturation such as neurogenesis and myelination. Co-expression networks further identified Zbtb16-correlated modules that are unique to ASD or SCZ respectively. Our study provides insight into the differential role of ZBTB16 in ASD and SCZ.

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Section: Discussionmentioning

confidence: 92%

Zbtb16regulates social cognitive behaviors and neocortical development

Usui

Berto

Konishi

et al. 2020

Preprint

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“…Given our primary goal to gain rst insight how Tcf4 haploinsu ciency, which has been causally linked to neurodevelopmental disorders such as Pitt-Hopkins Syndrome and intellectual disability, affects adult neurogenesis, we analysed constitutive heterozygote Tcf4 knockout mice. TCF4 expression is broadly expressed and is critical for the development of a number of neural and non-neural cell types (18,(45)(46)(47)(48). It therefore remains to be determined how decreased TCF4 dosage in different cell populations contribute to the impairment in adult hippocampal neurogenesis.…”

Section: Discussionmentioning

confidence: 99%

Enriched Environment Ameliorates Adult Hippocampal Neurogenesis Deficits in Tcf4 Haploinsufficient Mice

Braun

Häberle

Wittmann

et al. 2020

Preprint

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Background: Transcription factor 4 (TCF4) has been linked to human neurodevelopmental disorders such as intellectual disability, Pitt-Hopkins Syndrome (PTHS), autism, and schizophrenia. Recent work demonstrated that TCF4 participates in the control of a wide range of neurodevelopmental processes in mammalian nervous system development including neural precursor proliferation, timing of differentiation, migration, dendritogenesis and synapse formation. TCF4 is highly expressed in the adult hippocampal dentate gyrus – one of the few brain regions where neural stem / progenitor cells generate new functional neurons throughout life.Results: We here investigated whether TCF4 haploinsufficiency, which in humans causes non-syndromic forms of intellectual disability and PTHS, affects adult hippocampal neurogenesis, a process that is essential for hippocampal plasticity in rodents and potentially in humans. Young adult Tcf4 heterozygote knockout mice showed a major reduction in the level of adult hippocampal neurogenesis, which was at least in part caused by lower stem/progenitor cell numbers and impaired maturation and survival of adult-generated neurons. Interestingly, housing in an enriched environment was sufficient to enhance maturation and survival of new neurons and to substantially augment neurogenesis levels in Tcf4 heterozygote knockout mice.Conclusion: Haploinsufficiency for the transcription factor TCF4 has been linked to non-syndromic intellectual disability and PTHS. The present findings raise the possibility that TCF4 haploinsufficiency may have a continuous negative impact on hippocampal function by impeding hippocampal neurogenesis and suggest that behavioural stimulation may be harnessed to ameliorate a subset of TCF4 haploinsufficiency associated neural deficits during adulthood.

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“…Given our primary goal to gain rst insight how Tcf4 haploinsu ciency, which has been causally linked to neurodevelopmental disorders such as Pitt-Hopkins Syndrome and intellectual disability, affects adult neurogenesis, we analysed constitutive heterozygote Tcf4 knockout mice. TCF4 is broadly expressed and is critical for the development of a number of neural and non-neural cell types (18,(45)(46)(47)(48). It therefore remains to be determined how decreased TCF4 dosage in different cell populations contributes to the impairment in adult hippocampal neurogenesis.…”

Section: Discussionmentioning

confidence: 99%

Enriched environment ameliorates adult hippocampal neurogenesis deficits in Tcf4 haploinsufficient mice

Braun

Häberle

Wittmann

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Transcription factor 4 (TCF4) has been linked to human neurodevelopmental disorders such as intellectual disability, Pitt-Hopkins Syndrome (PTHS), autism, and schizophrenia. Recent work demonstrated that TCF4 participates in the control of a wide range of neurodevelopmental processes in mammalian nervous system development including neural precursor proliferation, timing of differentiation, migration, dendritogenesis and synapse formation. TCF4 is highly expressed in the adult hippocampal dentate gyrus – one of the few brain regions where neural stem / progenitor cells generate new functional neurons throughout life.Results: We here investigated whether TCF4 haploinsufficiency, which in humans causes non-syndromic forms of intellectual disability and PTHS, affects adult hippocampal neurogenesis, a process that is essential for hippocampal plasticity in rodents and potentially in humans. Young adult Tcf4 heterozygote knockout mice showed a major reduction in the level of adult hippocampal neurogenesis, which was at least in part caused by lower stem/progenitor cell numbers and impaired maturation and survival of adult-generated neurons. Interestingly, housing in an enriched environment was sufficient to enhance maturation and survival of new neurons and to substantially augment neurogenesis levels in Tcf4 heterozygote knockout mice.Conclusion: The present findings indicate that haploinsufficiency for the intellectual disability- and PTHS-linked transcription factor TCF4 not only affects embryonic neurodevelopment but impedes neurogenesis in the hippocampus of adult mice. These findings suggest that TCF4 haploinsufficiency may have a negative impact on hippocampal function throughout adulthood by impeding hippocampal neurogenesis.

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A myelin-related transcriptomic profile is shared by Pitt–Hopkins syndrome models and human autism spectrum disorder

Cited by 116 publications

References 71 publications

Zbtb16regulates social cognitive behaviors and neocortical development

Zbtb16regulates social cognitive behaviors and neocortical development

Enriched Environment Ameliorates Adult Hippocampal Neurogenesis Deficits in Tcf4 Haploinsufficient Mice

Enriched environment ameliorates adult hippocampal neurogenesis deficits in Tcf4 haploinsufficient mice

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