TGF  Signaling Regulates the Timing of CNS Myelination by Modulating Oligodendrocyte Progenitor Cell Cycle Exit through SMAD3/4/FoxO1/Sp1

Palazuelos, Javier; Klingener, Michael; Aguirre, Adán

doi:10.1523/jneurosci.0363-14.2014

Cited by 86 publications

(83 citation statements)

References 46 publications

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“…Low mRNA levels of miR-21 targets SOX-5 and TGFBR2 in the aggregated psychiatric subjects may indicate disrupted regulation of myelin formation (Palazuelos, Klingener, & Aguirre, 2014; Wegner, 2008), particularly on the case of Sox5. Sox5 together with other Sox-family factors regulates oligodendrocyte differentiation (Wegner, 2008).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-21: Expression in oligodendrocytes and correlation with low myelin mRNAs in depression and alcoholism

Miguel-Hidalgo

Hall

Bonner

et al. 2017

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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MiR-21 is a microRNA implicated in cancer, development, and cardiovascular diseases and expressed in the central nervous system (CNS), especially after injury. However, the cellular expression of miR-21 in the adult CNS has not been clearly established either in mice or human subjects, while its alteration in psychiatric disorders is unknown. MiR-21 expression was characterized in reporter mice expressing β–galactosidase (LacZ) under the endogenous miR-21 promoter (miR-21/LacZ). Brain co-localization of miR-21/LacZ with specific neural markers was examined by double immunofluorescence in reporter mice, while extent of immunostaining for myelin basic protein and PDGFRα was determined in miR-21 knockout and wild-type mice. Levels of miR-21, and mRNAs of selected miR-21 targets, miR-21 regulator STAT3 and myelin-related proteins were measured by qRT-PCR in the white matter (WM) adjacent to the left postmortem orbitofrontal cortex (OFC) of human subjects with major depressive disorder (MDD), alcoholism, comorbid MDD plus alcoholism (MDA) and non-psychiatric control subjects. MiR-21/LacZ was highly expressed in cell bodies of WM and myelinated portions of gray matter (GM). Labeled cell bodies were identified as oligodendrocytes, while miR-21/LacZ was barely detectable in other cell types. MiR-21, as well as the mRNAs of several myelin-related proteins, were reduced in the WM of subjects with MDD and alcoholism. MiR-21 positively correlated with mRNA of myelin-related proteins and astrocytic GFAP. High expression of miR-21 in adult oligodendrocytes and the correlation of miR-21 decrease with mRNA of some myelin proteins, regulator STAT3, and oligodendrocyte-related transcription factors suggest an involvement of miR-21 in WM alterations in depression and alcoholism.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-21: Expression in oligodendrocytes and correlation with low myelin mRNAs in depression and alcoholism

Miguel-Hidalgo

Hall

Bonner

et al. 2017

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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“…In a mouse model of chronic neonatal hypoxia, FoxO1 was shown to promote OPC proliferation (48). It is thus interesting to note that TGF-β signaling regulates the timing of myelination by mediating interactions between FoxO1 and Sp1, another TF that regulates OPC maturation (49). Wnt signaling is another negative regulator of OPC maturation during WMI that also downregulates Sp1-mediated transcription (50).…”

Section: Foxo3 Expression Is Markedly Increased In Oligodendroglia Inmentioning

confidence: 99%

A TLR/AKT/FoxO3 immune tolerance–like pathway disrupts the repair capacity of oligodendrocyte progenitors

Srivastava¹,

Diba²,

Dean³

et al. 2018

Journal of Clinical Investigation

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ers by interactions of FoxO3 with the chromatin-remodeling factor Brg1 and the TF Olig2, which are involved in control of OPC differentiation (14-16). Hence, central myelination failure is regulated by a noncanonical TLR4/AKT/FoxO3 signaling pathway utilized by bHAf to induce a tolerance-like state that selectively constrains OPC maturation and myelination. ResultsNeonatal hypoxic-ischemic WMI promotes MDa HA depolymerization. To investigate the status of MDa HA in chronic neonatal WMI, we employed our preterm-equivalent rat hypoxia-ischemia (H-I) model, which generates myelination failure and replicates key features of human WMI ( Figure 1A) (17). MDa HA turnover in the ECM after H-I was visualized with a biotinylated HA-binding protein (HABP) and costained with glial fibrillary acidic protein (GFAP) as a marker of WMI. Unlike in age-matched uninpro-myelination signal (13). This tolerance-like action of bHAf was mediated through TLR4 but not via CD44 or TLR2. As in TLR4-mediated IT, bHAf 's influence on myelination was reversible when MDa HA depolymerization was attenuated or bHAf was removed. AKT desensitization was similarly reversible in vivo in neonatal WMI. Moreover, bHAf actions were mediated via a noncanonical TRIF-dependent pathway, also involved in IT, rather than the canonical MyD88 arm of TLR4 signaling. AKT desensitization resulted in maturation-dependent activation of the FoxO3 transcription factor (TF), which selectively constrained preOL maturation in a bHAf-dependent fashion. A role for activated FoxO3 in human myelination failure was supported by selective localization of nuclear FoxO3 to OPCs in human preterm WMI and multiple sclerosis (MS) plaques. bHAf-mediated OPC maturation arrest appears to be regulated at the FoxO3 and myelin basic protein (MBP) promot- (Contralateral). Only the lesion group had a significant reduction in HA recovery. (E) Incubation of MDa HA with the lesion lysate generated HAf below ~650 kDa. Lesion-lysate activity was sensitive to heat inactivation but insensitive to deferoxamine (50 μM). B and C: control n = 2; H-I n = 4 animals for each age group (P4 and P14). D: n = 6 (H-I), n = 5 (control), and n = 4 (hypoxia) animals (P7). E: n = 4 separate experiments on 4 different animals at P4 after H-I at P3; one representative experiment is shown. *P < 0.05 by ANOVA. Mean ± SD. Scale bars: 300 μm (B and C). The Journal of Clinical Investigation R E S E A R C H A R T I C L E2 0 2 7 jci.orgVolume 128 Number 5 May 2018 with MBP-labeled oligodendrocytes (Supplemental Figure 2A). To confirm de novo progressive myelin generation, we undertook ultrastructural studies that identified axons wrapped with multilamellar myelin sheaths ( Figure 2B). In contrast to vehicle-treated slices, which displayed robust myelination of the corpus callosum, slices incubated with MDa HA until 21 days in vitro (DIV21) displayed a pronounced reduction in myelinated axons ( Figure 2C). Myelination failure was not related to decreased OPC survival, since MDa HA treatment did not enhance OPC degeneratio...

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“…With respect to schizophrenia, the pathway regulates oligodendrocyte maturation and differentiation (McKinnon et al, 1993; Palazuelos et al, 2014). It also participates in the development of connective tissues (Ilouz et al, 2002; Marger et al, 2014).…”

Section: Zip Proteins and The Slc39a13 Mutationmentioning

confidence: 99%

The Emerging Role for Zinc in Depression and Psychosis

et al. 2017

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Zinc participation is essential for all physiological systems, including neural functioning, where it participates in a myriad of cellular processes. Converging clinical, molecular, and genetic discoveries illuminate key roles for zinc homeostasis in association with clinical depression and psychosis which are not yet well appreciated at the clinical interface. Intracellular deficiency may arise from low circulating zinc levels due to dietary insufficiency, or impaired absorption from aging or medical conditions, including alcoholism. A host of medications commonly administered to psychiatric patients, including anticonvulsants, oral medications for diabetes, hormones, antacids, anti-inflammatories and others also impact zinc absorption. Furthermore, inefficient genetic variants in zinc transporter molecules that transport the ion across cellular membranes impede its action even when circulating zinc concentrations is in the normal range. Well powered clinical studies have shown beneficial effects of supplemental zinc in depression and it important to pursue research using zinc as a potential therapeutic option for psychosis as well. Meta-analyses support the adjunctive use of zinc in major depression and a single study now supports zinc for psychotic symptoms. This manuscript reviews the biochemistry and bench top evidence on putative molecular mechanisms of zinc as a psychiatric treatment.

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TGF Signaling Regulates the Timing of CNS Myelination by Modulating Oligodendrocyte Progenitor Cell Cycle Exit through SMAD3/4/FoxO1/Sp1

Cited by 86 publications

References 46 publications

MicroRNA-21: Expression in oligodendrocytes and correlation with low myelin mRNAs in depression and alcoholism

MicroRNA-21: Expression in oligodendrocytes and correlation with low myelin mRNAs in depression and alcoholism

A TLR/AKT/FoxO3 immune tolerance–like pathway disrupts the repair capacity of oligodendrocyte progenitors

The Emerging Role for Zinc in Depression and Psychosis

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