Independent and cooperative roles of the Mek/ERK1/2-MAPK and PI3K/Akt/mTOR pathways during developmental myelination and in adulthood
| Autor: | Akihiro Ishii, Rashmi Bansal, Wendy B. Macklin, Miki Furusho |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Male
MAP Kinase Signaling System Mice Transgenic mTORC1 Biology Nerve Fibers Myelinated Article Cellular and Molecular Neuroscience Myelin Mice Phosphatidylinositol 3-Kinases medicine Animals Remyelination Protein kinase B PI3K/AKT/mTOR pathway Myelin Sheath TOR Serine-Threonine Kinases Oligodendrocyte differentiation Age Factors MAP Kinase Kinase Kinases Oligodendrocyte Mice Inbred C57BL medicine.anatomical_structure Neurology Myelinogenesis Female Neuroscience Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Glia. 67(7) |
| ISSN: | 1098-1136 |
| Popis: | Multiple extracellular and intracellular signals regulate the functions of oligodendrocytes as they progress through the complex process of developmental myelination and then maintain a functionally intact myelin sheath throughout adult life, preserving the integrity of the axons. Recent studies suggest that Mek/ERK1/2-MAPK and PI3K/Akt/mTOR intracellular signaling pathways play important, often overlapping roles in the regulation of myelination. However, it remains poorly understood whether they function independently, sequentially, or converge using a common mechanism to facilitate oligodendrocyte differentiation, myelin growth, and maintenance. To address these questions, we analyzed multiple genetically modified mice and asked whether the deficits due to the conditional loss-of-function of ERK1/2 or mTOR could be abrogated by simultaneous constitutive activation of PI3K/Akt or Mek, respectively. From these studies, we concluded that while PI3K/Akt, not Mek/ERK1/2, plays a key role in promoting oligodendrocyte differentiation and timely initiation of myelination through mTORC1 signaling, Mek/ERK1/2-MAPK functions largely independently of mTORC1 to preserve the integrity of the myelinated axons during adulthood. However, to promote the efficient growth of the myelin sheath, these two pathways cooperate with each other converging at the level of mTORC1, both in the context of normal developmental myelination or following forced reactivation of the myelination program during adulthood. Thus, Mek/ERK1/2-MAPK and the PI3K/Akt/mTOR signaling pathways work both independently and cooperatively to maintain a finely tuned, temporally regulated balance as oligodendrocytes progress through different phases of developmental myelination into adulthood. Therapeutic strategies aimed at targeting remyelination in demyelinating diseases are expected to benefit from these findings. |
| Databáze: | OpenAIRE |
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