Activation of Shh/Smo is sufficient to maintain oligodendrocyte precursor cells in an undifferentiated state and is not necessary for myelin formation and (re)myelination.

Autor: Nocera S; Grupo de Neurobiología del Desarrollo-GNDe, Instituto Cajal-CSIC, Madrid, Spain., Marchena MA; Grupo de Neurobiología del Desarrollo-GNDe, Instituto Cajal-CSIC, Madrid, Spain.; Facultad HM de Ciencias de la Salud de la UCJC, Universidad Camilo José Cela, Madrid, Spain.; NeuroLab, Instituto de Investigación Sanitaria HM Hospitales, Madrid, Spain., Fernández-Gómez B; Grupo de Neurobiología del Desarrollo-GNDe, Instituto Cajal-CSIC, Madrid, Spain., Gómez-Martín P; Grupo de Neurobiología del Desarrollo-GNDe, Instituto Cajal-CSIC, Madrid, Spain., Sánchez-Jiménez E; Grupo de Neurobiología del Desarrollo-GNDe, Instituto Cajal-CSIC, Madrid, Spain., Macías-Castellano A; Grupo de Neurobiología del Desarrollo-GNDe, Instituto Cajal-CSIC, Madrid, Spain., Laó Y; Grupo de Neurobiología del Desarrollo-GNDe, Instituto Cajal-CSIC, Madrid, Spain., Cordano C; Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, California, USA.; Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health. University of Genoa, Italy.; Department of Neuroscience, IRCCS Ospedale Policlinico San Martino, Genoa, Italy., Gómez-Torres Ó; Facultad de Ciencias Ambientales, Universidad de Castilla-La Mancha, Toledo, Spain., Luján R; Facultad de Medicina, Universidad de Castilla-La Mancha, Albacete, Spain., de Castro F; Grupo de Neurobiología del Desarrollo-GNDe, Instituto Cajal-CSIC, Madrid, Spain.
Jazyk: angličtina
Zdroj: Glia [Glia] 2024 Aug; Vol. 72 (8), pp. 1469-1483. Date of Electronic Publication: 2024 May 21.
DOI: 10.1002/glia.24540
Abstrakt: Myelination is the terminal step in a complex and precisely timed program that orchestrates the proliferation, migration and differentiation of oligodendroglial cells. It is thought that Sonic Hedgehog (Shh) acting on Smoothened (Smo) participates in regulating this process, but that these effects are highly context dependent. Here, we investigate oligodendroglial development and remyelination from three specific transgenic lines: NG2-Cre ERT2 (control), Smo fl/fl /NG2-Cre ERT2 (loss of function), and SmoM2/NG2-Cre ERT2 (gain of function), as well as pharmacological manipulation that enhance or inhibit the Smo pathway (Smoothened Agonist (SAG) or cyclopamine treatment, respectively). To explore the effects of Shh/Smo on differentiation and myelination in vivo, we developed a highly quantifiable model by transplanting oligodendrocyte precursor cells (OPCs) in the retina. We find that myelination is greatly enhanced upon cyclopamine treatment and hypothesize that Shh/Smo could promote OPC proliferation to subsequently inhibit differentiation. Consistent with this hypothesis, we find that the genetic activation of Smo significantly increased numbers of OPCs and decreased oligodendrocyte differentiation when we examined the corpus callosum during development and after cuprizone demyelination and remyelination. However, upon loss of function with the conditional ablation of Smo, myelination in the same scenarios are unchanged. Taken together, our present findings suggest that the Shh pathway is sufficient to maintain OPCs in an undifferentiated state, but is not necessary for myelination and remyelination.
(© 2024 The Authors. GLIA published by Wiley Periodicals LLC.)
Databáze: MEDLINE
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