Neuronal CTGF/CCN2 negatively regulates myelination in a mouse model of tuberous sclerosis complex.
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 neuronalTsc1have 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-specificTsc1deletion 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.
Department of Neurology, F.M. Kirby Center for Neurobiology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
Ebru
E
Ercan
Department of Neurology, F.M. Kirby Center for Neurobiology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
Juliette M
JM
Han
Department of Neurology, F.M. Kirby Center for Neurobiology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
Alessia
0000-0002-0025-7290
A
Di Nardo
Department of Neurology, F.M. Kirby Center for Neurobiology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
Kellen
K
Winden
Department of Neurology, F.M. Kirby Center for Neurobiology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.|Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
Min-Joon
MJ
Han
Department of Neurology, F.M. Kirby Center for Neurobiology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.|Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
Leonie
L
Hoyo
Department of Neurology, F.M. Kirby Center for Neurobiology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
Afshin
0000-0003-4119-7519
A
Saffari
Department of Dentistry, Schulich School of Medicine and Dentistry, London, Ontario N6A 5C1, Canada.|Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, London, Ontario N6A 5C1, Canada.
Andrew
0000-0003-2832-283X
A
Leask
Department of Neurology, University of California, Los Angeles School of Medicine, Los Angeles, CA 90095.|Semel Institute, University of California, Los Angeles School of Medicine, Los Angeles, CA 90095.|Department of Human Genetics, University of California, Los Angeles School of Medicine, Los Angeles, CA 90095.
Daniel H
DH
Geschwind
Department of Neurology, F.M. Kirby Center for Neurobiology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115 mustafa.sahin@childrens.harvard.edu.|Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
Mustafa
0000-0001-7044-2953
M
Sahin
D000818:Animals; D055513:Connective Tissue Growth Factor / Q000502:physiology*; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D009186:Myelin Sheath / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D009836:Oligodendroglia / Q000502:physiology; D051381:Rats; D058570:TOR Serine-Threonine Kinases / Q000502:physiology; D014402:Tuberous Sclerosis / Q000503:physiopathology*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000502:physiology
C526318:CCN2 protein, mouse; C000624650:TSC1 protein, human; C000624651:Tsc1 protein, mouse; C000624652:Tsc1 protein, rat; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D055513:Connective Tissue Growth Factor; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases