Hypomyelination following deletion of Tsc2 in oligodendrocyte precursors

Abstract

ObjectiveWhile 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.MethodsTo 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.ResultsCharacterization 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.InterpretationOur findings support a known role of mTOR signaling in regulation of myelination and demonstrate that increased mTORC1 activity early in development within oligodendrocytes results in hypomyelination and not hypermyelination. Our data further support a dissociation between decreased Akt activity and increased mTORC1 activity toward hypomyelination. Thus, therapies promoting activation of Akt‐dependent pathways while reducing mTORC1 activity may prove beneficial in treatment of human disease.

Myelination and mTOR

“…Hypomyelination and a reduction in OL‐lineage cells were also reported after deletion of TSC2 (Carson et al, 2015). These results are in line with reports of abnormal white matter microstructure in the brain of patients with tuberous sclerosis, a systemic disorder caused by loss‐of‐function mutations of TSC1 or TSC2 (Ercan et al, 2017).…”

“…However, because treatment with rapamycin was able to reverse the impaired myelination in the PNS and CNS (Beirowski et al, 2017; Carson et al, 2015; Figlia et al, 2017; Jiang et al, 2016; Lebrun‐Julien et al, 2014), this possibility seems unlikely.…”

“…The major outcomes of the loss‐ and gain‐of‐function studies on the roles of mTORC1 and the upstream PI3K‐Akt and Mek‐Erk1/2 pathways in PNS and CNS myelination are summarized (Beirowski et al, 2017; Bercury et al, 2014; Carson et al, 2015; Cotter et al, 2010; Domenech‐Estevez et al, 2016; Figlia et al, 2017; Flores et al, 2008; Fyffe‐Maricich, Karlo, Landreth, & Miller, 2011; Fyffe‐Maricich, Schott, Karl, Krasno, & Miller, 2013; Goebbels et al, 2010, 2012; Ishii, Furusho, & Bansal, 2013; Ishii, Furusho, Dupree, & Bansal, 2016; Jeffries et al, 2016; Jiang et al, 2016; Lebrun‐Julien et al, 2014; Napoli et al, 2012; Newbern et al, 2011; Norrmén et al, 2014; Sheean et al, 2014; Sherman et al, 2012; Wahl et al, 2014; Zou et al, 2011, 2014)…”

“…Although the interpretation of the available evidence is somewhat complex due to variable experimental strategies used, the combined findings suggest that, in contrast to hyperactivation of mTORC1 following deletion of TSC1 or TSC2 (Beirowski et al, 2017; Carson et al, 2015; Figlia et al, 2017; Jiang et al, 2016; Lebrun‐Julien et al, 2014), hyperactivation of Mek‐Erk1/2 using constitutively active Mek1 causes radial hypermyelination, both in the CNS and PNS (Fyffe‐Maricich et al, 2013; Ishii et al, 2013, 2016; Sheean et al, 2014). However, the mTORC1‐independent targets of Mek‐Erk1/2 that may be responsible for the differences observed by activation of these signaling pathways are unknown.…”

Os produtos dos genes Tsc1 e Tsc2 em processos neurodegenerativos

“…Nesta linha de raciocínio, estudos recentes com camundongos geneticamente modificados têm examinado os efeitos da deleção condicional de Tsc1 ou Tsc2 em áreas ou células específicos do sistema nervoso, a maioria com enfoque em precursores neurogliais que formarão o córtex cerebral (CARSON et al, 2011(CARSON et al, , 2015CROWELL et al, 2015;ERBAYAT-ALTAY et al, 2007;ESS et al, 2004;FU et al, 2012;JONES et al, 2015;MCMAHON et al, 2012;NIE et al, 2015;UHLMANN et al, 2002;WANG et al, 2007;YUAN et al, 2012;ZENG et al, 2011). A deleção de Tsc1 no décimo terceiro dia embrionário, especificamente em células do tálamo, afeta o circuito talamocortical (NORMAND et al, 2013), indicando que outras estruturas cerebrais podem ser vulneráveis à redução de dose de TSC1 ou TSC2.…”