Neuronal CTGF/CCN2 negatively regulates myelination in a mouse model of tuberous sclerosis complex.
Ebru ErcanJuliette M HanAlessia Di NardoKellen WindenMin-Joon HanLeonie HoyoAfshin SaffariAndrew LeaskDaniel H GeschwindMustafa SahinPublished in: The Journal of experimental medicine (2017)
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.
Keyphrases
- growth factor
- white matter
- cerebral ischemia
- mouse model
- genome wide
- autism spectrum disorder
- multiple sclerosis
- stem cells
- single cell
- type diabetes
- radiation therapy
- intellectual disability
- insulin resistance
- spinal cord injury
- dna methylation
- subarachnoid hemorrhage
- signaling pathway
- oxidative stress
- sensitive detection
- brain injury
- blood brain barrier
- cell therapy
- metabolic syndrome
- copy number