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Neuronal deletion of Gtf2i, associated with Williams syndrome, causes behavioural and myelin alterations rescuable by a remyelinating drug

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE128841 | GEO | 2019/03/26

REPOSITORIES: GEO

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Neuronal deletion of Gtf2i, associated with Williams syndrome, causes behavioural and myelin alterations rescuable by a remyelinating drug [human]

Project description:Williams syndrome (WS), caused by a heterozygous microdeletion in 7q11.23, is a neurodevelopmental disorder characterized by hypersociability and neurocognitive abnormalities. Of the deleted genes, general transcription factor II-i (Gtf2i) has been linked to hypersociability in WS, though the underlying mechanisms are poorly understood. We show that selective deletion of Gtf2i in forebrain excitatory neurons caused neuroanatomical defects, fine motor deficits, increased sociability and anxiety. Unexpectedly, 70% of the genes with significantly decreased mRNA levels in the mutant mouse cortex are involved in myelination, and mutant mice had reduced mature oligodendrocyte cell numbers, reduced myelin thickness and impaired axonal conductivity. Restoring myelination properties with clemastine or increasing axonal conductivity rescued the behavioural deficits. Frontal cortex from WS patients similarly showed reduced myelin thickness, mature oligodendrocyte cell numbers and mRNA levels of myelination-related genes. Our study provides molecular and cellular evidence for myelination deficits in WS linked to neuronal deletion of Gtf2i.

2019-03-26 | GSE128840 | GEO

Neuronal deletion of Gtf2i, associated with Williams syndrome, causes behavioural and myelin alterations rescuable by a remyelinating drug [mouse P30]

2019-03-26 | GSE128839 | GEO

Neuronal deletion of Gtf2i, associated with Williams syndrome, causes behavioural and myelin alterations rescuable by a remyelinating drug [mouse P1]

2019-03-26 | GSE128838 | GEO

Neuronal deletion of Gtf2i, associated with Williams syndrome, causes behavioural and myelin alterations rescuable by a remyelinating drug

Project description:Neuronal deletion of Gtf2i, associated with Williams syndrome, causes behavioural and myelin alterations rescuable by a remyelinating drug

| PRJNA529019 | ENA

Neuronal deletion of Gtf2i, associated with Williams syndrome, causes behavioural and myelin alterations rescuable by a remyelinating drug [human]

Project description:Neuronal deletion of Gtf2i, associated with Williams syndrome, causes behavioural and myelin alterations rescuable by a remyelinating drug [human]

| PRJNA529023 | ENA

Neuronal deletion of Gtf2i, associated with Williams syndrome, causes behavioural and myelin alterations rescuable by a remyelinating drug [mouse P1]

Project description:Neuronal deletion of Gtf2i, associated with Williams syndrome, causes behavioural and myelin alterations rescuable by a remyelinating drug [mouse P1]

| PRJNA529020 | ENA

Neuronal deletion of Gtf2i, associated with Williams syndrome, causes behavioural and myelin alterations rescuable by a remyelinating drug [mouse P30]

Project description:Neuronal deletion of Gtf2i, associated with Williams syndrome, causes behavioural and myelin alterations rescuable by a remyelinating drug [mouse P30]

| PRJNA529021 | ENA

Inefficient clearance of myelin debris by microglia impairs remyelinating processes.

Project description:An imbalance between remyelinating and demyelinating rates underlies degenerative processes in demyelinating diseases such as multiple sclerosis. An optimal therapeutic strategy would be to stimulate remyelination while limiting demyelination. Although accumulation of myelin debris impairs remyelination, the mechanisms regulating the clearance of such debris by mononuclear phagocytic cells are poorly understood. We demonstrate that after cuprizone intoxication, CCR2-dependent infiltration of mouse bone marrow-derived cells is abundant in demyelinating areas, but that these cells do not impact demyelination. However, in CX3CR1-deficient mice, the clearance of myelin debris by microglia was blocked greatly, affecting the integrity of the axon and myelin sheaths and thus preventing proper remyelination. These results highlight the crucial role played by CX3CR1 in myelin removal and show that there can be no efficient remyelination after a primary demyelinating insult if myelin clearance by microglia is impaired.

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Neuronal Gtf2i deletion alters mitochondrial and autophagic properties.

Project description:Gtf2i encodes the general transcription factor II-I (TFII-I), with peak expression during pre-natal and early post-natal brain development stages. Because these stages are critical for proper brain development, we studied at the single-cell level the consequences of Gtf2i's deletion from excitatory neurons, specifically on mitochondria. Here we show that Gtf2i's deletion resulted in abnormal morphology, disrupted mRNA related to mitochondrial fission and fusion, and altered autophagy/mitophagy protein expression. These changes align with elevated reactive oxygen species levels, illuminating Gtf2i's importance in neurons mitochondrial function. Similar mitochondrial issues were demonstrated by Gtf2i heterozygous model, mirroring the human condition in Williams syndrome (WS), and by hemizygous neuronal Gtf2i deletion model, indicating Gtf2i's dosage-sensitive role in mitochondrial regulation. Clinically relevant, we observed altered transcript levels related to mitochondria, hypoxia, and autophagy in frontal cortex tissue from WS individuals. Our study reveals mitochondrial and autophagy-related deficits shedding light on WS and other Gtf2i-related disorders.

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The Williams syndrome prosociality gene GTF2I mediates oxytocin reactivity and social anxiety in a healthy population.

Project description:The neurohormone oxytocin plays a central role in human social behaviour and cognition, and oxytocin dysregulation may contribute to psychiatric disorders. However, genetic factors influencing individual variation in the oxytocinergic system remain poorly understood. We genotyped 169 healthy adults for a functional polymorphism in GTF2I (general transcription factor II-I), a gene associated with high prosociality and reduced social anxiety in Williams syndrome, a condition reported to involve high oxytocin levels and reactivity. Participants' salivary oxytocin levels were measured before and after watching a validated empathy-inducing video. Oxytocin reactivity, defined as pre- to post-video percentage change in salivary oxytocin, varied substantially and significantly between individuals with different GTF2I genotypes, with, additionally, a trend towards an interaction between genotype and sex. Individuals with more oxytocin-reactive genotypes also reported significantly lower social anxiety. These findings suggest a model whereby GTF2I has a continuum of effects on human sociality, from the extreme social phenotypes and oxytocin dysregulation associated with gene deletion in Williams syndrome, to individual differences in oxytocin reactivity and sociality associated with common polymorphisms in healthy populations.

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