Open AccessHypomyelination following deletion of Tsc2 in oligodendrocyte precursors
Author(s) -
Carson Robert P.,
Kelm Nathaniel D.,
West Kathryn L.,
Does Mark D.,
Fu Cary,
Weaver Grace,
McBrier Eleanor,
Parker Brittany,
Grier Mark D.,
Ess Kevin C.
Publication year - 2015
Publication title -
annals of clinical and translational neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.824
H-Index - 42
ISSN - 2328-9503
DOI - 10.1002/acn3.254
Subject(s) - oligodendrocyte , myelin , tsc2 , protein kinase b , conditional gene knockout , pi3k/akt/mtor pathway , neuroscience , olig2 , white matter , myelin basic protein , gliosis , biology , microbiology and biotechnology , phenotype , cancer research , signal transduction , medicine , magnetic resonance imaging , central nervous system , genetics , gene , radiology
Objective While abnormalities in myelin in tuberous sclerosis complex ( TSC ) have been known for some time, recent imaging‐based data suggest myelin abnormalities may be independent of the pathognomonic cortical lesions (“tubers”). Multiple mouse models of TSC exhibit myelination deficits, though the cell types responsible and the mechanisms underlying the myelin abnormalities remain unclear. Methods To determine the role of alterations in mTOR signaling in myelination, we generated a conditional knockout ( CKO ) mouse model using Cre‐recombinase and the Olig2 promoter to inactivate the Tsc2 gene in oligodendrocyte precursor cells. Results Characterization of myelin and myelin constituent proteins demonstrated a marked hypomyelination phenotype. Diffusion‐based magnetic resonance imaging studies were likewise consistent with hypomyelination. Hypomyelination was due in part to decreased myelinated axon density and myelin thickness as well as decreased oligodendrocyte numbers. Coincident with hypomyelination, an extensive gliosis was seen in both the cortex and white matter tracks, suggesting alterations in cell fate due to changes in mTOR activity in oligodendrocyte precursors. Despite a high‐frequency appendicular tremor and altered gait in CKO mice, no significant changes in activity, vocalizations, or anxiety‐like phenotypes were seen. Interpretation Our findings support a known role of mTOR signaling in regulation of myelination and demonstrate that increased mTORC 1 activity early in development within oligodendrocytes results in hypomyelination and not hypermyelination. Our data further support a dissociation between decreased Akt activity and increased mTORC 1 activity toward hypomyelination. Thus, therapies promoting activation of Akt‐dependent pathways while reducing mTORC 1 activity may prove beneficial in treatment of human disease.