Δ 9 ‐Tetrahydrocannabinol promotes oligodendrocyte development and CNS myelination in vivo

Abstract Background Myelination is a highly regulated process in the vertebrate central nervous system (CNS) whereby oligodendrocytes wrap axons with multiple layers of insulating myelin in order to allow rapid electrical conduction. Establishing the proper pattern of myelin in neural circuits requires communicative axo-glial interactions, however, the molecular interactions that occur between oligodendrocytes and axons during developmental myelination and myelin maintenance remain to be fully elucidated. Our previous work identified G protein-coupled receptor 62 (Gpr62), an uncharacterized orphan g-protein coupled receptor, as being selectively expressed by mature oligodendrocytes within the CNS, suggesting a potential role in myelination or axoglial interactions. However, no studies to date have assessed the functional requirement for Gpr62 in oligodendrocyte development or CNS myelination. Methods To address this, we generated a knockout mouse strain lacking the Gpr62 gene. We assessed CNS myelination during both postnatal development and adulthood using immunohistochemistry, electron microscopy and western blot. In addition, we utilized AAV-mediated expression of a tagged Gpr62 in oligodendrocytes to determine the subcellular localization of the protein in vivo. Results We find that virally expressed Gpr62 protein is selectively expressed on the adaxonal myelin layer, suggestive of a potential role for Gpr62 in axo-myelinic signaling. Nevertheless, Gpr62 knockout mice display normal oligodendrocyte numbers and apparently normal myelination within the CNS during both postnatal development and adulthood. Conclusions We conclude that in spite of being well-placed to mediate neuronal-oligodendrocyte communications, Gpr62 is overall dispensable for CNS myelination.

Download Full-text

TCF12 controls oligodendroglial cell proliferation and regulates signaling pathways conserved in gliomas

10.1101/2021.07.26.453859 ◽

2021 ◽

Author(s):

Sofia Archontidi ◽

Corentine Marie ◽

Beata Gyorgy ◽

Justine Guegan ◽

Marc Sanson ◽

...

Keyword(s):

Biological Processes ◽

Oligodendrocyte Differentiation ◽

Gene Encoding ◽

Genome Wide ◽

Diffuse Gliomas ◽

Mrna And Protein Expression ◽

Oligodendrocyte Precursor ◽

Oligodendrocyte Development ◽

Chromatin Profiling

Diffuse gliomas are primary brain tumors originating from the transformation of glial cells. In particular, oligodendrocyte precursor cells constitute the major tumor-amplifying population in the gliomagenic process. We previously identified the TCF12 gene, encoding a transcription factor of the E protein family, as being recurrently mutated in oligodendrogliomas. In this study, we sought to understand the function of TCF12 in oligodendroglial cells, the glioma lineage of origin. We first describe TCF12 mRNA and protein expression pattern in oligodendroglial development in the mouse brain. Second, by TCF12 genome wide chromatin profiling in oligodendroglial cells, we show that TCF12 binds active promoters of genes involved in proliferation, translation/ribosomes, and pathways involved in oligodendrocyte development and cancer. Finally, we perform OPC-specific Tcf12 inactivation in vivo and demonstrate by immunofluorescence and transcriptomic analyses that TCF12 is transiently required for OPC proliferation but dispensable for oligodendrocyte differentiation. We further show that Tcf12 inactivation results in deregulation of biological processes that are also altered in oligodendrogliomas. Together, our data suggest that TCF12 directly regulates transcriptional programs in oligodendroglia development that are relevant in a glioma context.

Download Full-text

Oligodendrocyte development and dysmyelinating diseases: Teneurin-4 as a novel regulator of CNS myelination

Neuroscience Research ◽

10.1016/j.neures.2011.07.108 ◽

2011 ◽

Vol 71 ◽

pp. e25-e26

Author(s):

Nobuharu Suzuki ◽

Eri Hirasawa ◽

Yoshihiko Yamada ◽

Chihiro Akazawa

Keyword(s):

Oligodendrocyte Development ◽

Cns Myelination

Download Full-text

Expression of Concern: Palazuelos et al., “TACE/ADAM17 is Essential for Oligodendrocyte Development and CNS Myelination”

Journal of Neuroscience ◽

10.1523/jneurosci.0611-21.2021 ◽

2021 ◽

pp. JN-ERR-0611-21

Keyword(s):

Oligodendrocyte Development ◽

Cns Myelination

Download Full-text

Transcription factor Tcf4 is the preferred heterodimerization partner for Olig2 in oligodendrocytes and required for differentiation

Nucleic Acids Research ◽

10.1093/nar/gkaa218 ◽

2020 ◽

Vol 48 (9) ◽

pp. 4839-4857 ◽

Cited By ~ 4

Author(s):

Miriam Wedel ◽

Franziska Fröb ◽

Olga Elsesser ◽

Marie-Theres Wittmann ◽

D Chichung Lie ◽

...

Keyword(s):

Ex Vivo ◽

Physical Interaction ◽

Functional Studies ◽

Basic Helix Loop Helix ◽

Helix Loop Helix ◽

Mouse Mutants ◽

Id Proteins ◽

A Cell ◽

Oligodendrocyte Development

Abstract Development of oligodendrocytes and myelin formation in the vertebrate central nervous system is under control of several basic helix-loop-helix transcription factors such as Olig2, Ascl1, Hes5 and the Id proteins. The class I basic helix-loop-helix proteins Tcf3, Tcf4 and Tcf12 represent potential heterodimerization partners and functional modulators for all, but have not been investigated in oligodendrocytes so far. Using mouse mutants, organotypic slice and primary cell cultures we here show that Tcf4 is required in a cell-autonomous manner for proper terminal differentiation and myelination in vivo and ex vivo. Partial compensation is provided by the paralogous Tcf3, but not Tcf12. On the mechanistic level Tcf4 was identified as the preferred heterodimerization partner of the central regulator of oligodendrocyte development Olig2. Both genetic studies in the mouse as well as functional studies on enhancer regions of myelin genes confirmed the relevance of this physical interaction for oligodendrocyte differentiation. Considering that alterations in TCF4 are associated with syndromic and non-syndromic forms of intellectual disability, schizophrenia and autism in humans, our findings point to the possibility of an oligodendroglial contribution to these disorders.

Download Full-text

Dynamic CCN3 expression in the murine CNS does not confer essential roles in myelination or remyelination

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1922089117 ◽

2020 ◽

Vol 117 (30) ◽

pp. 18018-18028

Author(s):

Nira de la Vega Gallardo ◽

Rosana Penalva ◽

Marie Dittmer ◽

Michelle Naughton ◽

John Falconer ◽

...

Keyword(s):

Spinal Cord ◽

Ex Vivo ◽

Matricellular Protein ◽

Suprachiasmatic Nuclei ◽

Dynamic Expression ◽

Ccn3 Expression ◽

Cns Myelination

CCN3 is a matricellular protein that promotes oligodendrocyte progenitor cell differentiation and myelination in vitro and ex vivo. CCN3 is therefore a candidate of interest in central nervous system (CNS) myelination and remyelination, and we sought to investigate the expression and role of CCN3 during these processes. We found CCN3 to be expressed predominantly by neurons in distinct areas of the CNS, primarily the cerebral cortex, hippocampus, amygdala, suprachiasmatic nuclei, anterior olfactory nuclei, and spinal cord gray matter. CCN3 was transiently up-regulated following demyelination in the brain of cuprizone-fed mice and spinal cord lesions of mice injected with lysolecithin. However, CCN3−/−mice did not exhibit significantly different numbers of oligodendroglia or differentiated oligodendrocytes in the healthy or remyelinating CNS, compared to WT controls. These results suggest that despite robust and dynamic expression in the CNS, CCN3 is not required for efficient myelination or remyelination in the murine CNS in vivo.

Download Full-text

Developmental pruning of early-stage myelin segments during CNS myelination in vivo

Cell Research ◽

10.1038/cr.2013.62 ◽

2013 ◽

Vol 23 (7) ◽

pp. 962-964 ◽

Cited By ~ 12

Author(s):

Peng Liu ◽

Jiu-lin Du ◽

Cheng He

Keyword(s):

Early Stage ◽

Cns Myelination

Download Full-text

Combinatorial actions of Tgf and Activin ligands promote oligodendrocyte development and CNS myelination

Development ◽

10.1242/dev.106492 ◽

2014 ◽

Vol 141 (12) ◽

pp. 2414-2428 ◽

Cited By ~ 17

Author(s):

D. J. Dutta ◽

A. Zameer ◽

J. N. Mariani ◽

J. Zhang ◽

L. Asp ◽

...

Keyword(s):

Oligodendrocyte Development ◽

Cns Myelination

Download Full-text

In vivo analysis of kallikrein-related peptidase 6 (KLK6) function in oligodendrocyte development and the expression of myelin proteins

Neuroscience ◽

10.1016/j.neuroscience.2012.12.073 ◽

2013 ◽

Vol 236 ◽

pp. 1-11 ◽

Cited By ~ 13

Author(s):

K. Murakami ◽

Y.-P. Jiang ◽

T. Tanaka ◽

Y. Bando ◽

B. Mitrovic ◽

...

Keyword(s):

Myelin Proteins ◽

In Vivo Analysis ◽

Oligodendrocyte Development

Download Full-text

THAP1 modulates oligodendrocyte maturation by regulating ECM degradation in lysosomes

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2100862118 ◽

2021 ◽

Vol 118 (31) ◽

pp. e2100862118

Author(s):

Dhananjay Yellajoshyula ◽

Samuel S. Pappas ◽

Abigail E. Rogers ◽

Biswa Choudhury ◽

Xylena Reed ◽

...

Keyword(s):

Central Nervous System ◽

Extracellular Matrix ◽

Nervous System ◽

Oligodendrocyte Progenitor Cells ◽

Gene Encoding ◽

A Cell ◽

Ecm Degradation ◽

Oligodendrocyte Development

Mechanisms controlling myelination during central nervous system (CNS) maturation play a pivotal role in the development and refinement of CNS circuits. The transcription factor THAP1 is essential for timing the inception of myelination during CNS maturation through a cell-autonomous role in the oligodendrocyte lineage. Here, we demonstrate that THAP1 modulates the extracellular matrix (ECM) composition by regulating glycosaminoglycan (GAG) catabolism within oligodendrocyte progenitor cells (OPCs). Thap1−/− OPCs accumulate and secrete excess GAGs, inhibiting their maturation through an autoinhibitory mechanism. THAP1 controls GAG metabolism by binding to and regulating the GusB gene encoding β-glucuronidase, a GAG-catabolic lysosomal enzyme. Applying GAG-degrading enzymes or overexpressing β-glucuronidase rescues Thap1−/− OL maturation deficits in vitro and in vivo. Our studies establish lysosomal GAG catabolism within OPCs as a critical mechanism regulating oligodendrocyte development.

Download Full-text