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

J Exp Med. 2017 Mar 6;214(3):681-697. doi: 10.1084/jem.20160446. Epub 2017 Feb 9.

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.

MeSH terms

  • Animals
  • Connective Tissue Growth Factor / physiology*
  • Disease Models, Animal
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Myelin Sheath / physiology*
  • Neurons / physiology*
  • Oligodendroglia / physiology
  • Rats
  • TOR Serine-Threonine Kinases / physiology
  • Tuberous Sclerosis / physiopathology*
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / physiology

Substances

  • CCN2 protein, mouse
  • TSC1 protein, human
  • Tsc1 protein, mouse
  • Tsc1 protein, rat
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • Connective Tissue Growth Factor
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse