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Neuronal CTGF/CCN2 negatively regulates myelination in a mouse model of tuberous sclerosis complex.


ABSTRACT: Disruption of myelination during development has been implicated in a range of neurodevelopmental disorders including tuberous sclerosis complex (TSC). TSC patients with autism display impairments in white matter integrity. Similarly, mice lacking neuronal Tsc1 have a hypomyelination phenotype. However, the mechanisms that underlie these phenotypes remain unknown. In this study, we demonstrate that neuronal TSC1/2 orchestrates a program of oligodendrocyte maturation through the regulated secretion of connective tissue growth factor (CTGF). We characterize oligodendrocyte maturation both in vitro and in vivo. We find that neuron-specific Tsc1 deletion results in an increase in CTGF secretion that non-cell autonomously stunts oligodendrocyte development and decreases the total number of oligodendrocytes. Genetic deletion of CTGF from neurons, in turn, mitigates the TSC-dependent hypomyelination phenotype. These results show that the mechanistic target of rapamycin (mTOR) pathway in neurons regulates CTGF production and secretion, revealing a paracrine mechanism by which neuronal signaling regulates oligodendrocyte maturation and myelination in TSC. This study highlights the role of mTOR-dependent signaling between neuronal and nonneuronal cells in the regulation of myelin and identifies an additional therapeutic avenue for this disease.

SUBMITTER: Ercan E 

PROVIDER: S-EPMC5339668 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Neuronal CTGF/CCN2 negatively regulates myelination in a mouse model of tuberous sclerosis complex.

Ercan Ebru E   Han Juliette M JM   Di Nardo Alessia A   Winden Kellen K   Han Min-Joon MJ   Hoyo Leonie L   Saffari Afshin A   Leask Andrew A   Geschwind Daniel H DH   Sahin Mustafa M  

The Journal of experimental medicine 20170209 3


Disruption of myelination during development has been implicated in a range of neurodevelopmental disorders including tuberous sclerosis complex (TSC). TSC patients with autism display impairments in white matter integrity. Similarly, mice lacking neuronal <i>Tsc1</i> have a hypomyelination phenotype. However, the mechanisms that underlie these phenotypes remain unknown. In this study, we demonstrate that neuronal TSC1/2 orchestrates a program of oligodendrocyte maturation through the regulated  ...[more]

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