In diseases of the central nervous system (CNS) such as Multiple Sclerosis (MS), myelinating cells are the principal affected cells. Following pathological loss of myelin, remyelination by oligodendrocyte precursors (OPC) occurs but becomes increasingly incomplete and eventually fails in the majority of lesions. Understanding the molecular basis of myelination and remyelination and the regulation of the cells that achieve myelination and remyelination is primordial for both fundamental and clinical research.
The host lab and others have shown, mainly using conditional transgenic approaches in mice, that Dicer, an enzyme responsible for the maturation of small RNAs, including miRNAs, is essential for correct development of myelinating cells and their interactions with neurons. However, the functional role of small RNAs in adult remyelination has not been explored. Thus, the ETH Fellow will examine the importance of Dicer and DGCR8 (the latter is required specifically for miRNA maturation) during remyelination after injury. To achieve this goal, we will use conditional floxed alleles in the mouse that target these two genes. In combination with a well characterized tamoxifen-inducible PDGFRα-CreERT2 allele, we will eliminate DGCR8 and Dicer specifically in adult oligodendrocytes precursors cells followed by spinal cord injection of lysolecithin, a well-controlled demyelination/remyelination model. In parallel and in collaboration with other lab members, the ETH fellow will perform complementary neuroprotection experiments using a suitable neuron-specific inducible Cre recombinase line combined with the Dicer or the DGCR8 conditional lines. The work is embedded firmly in ongoing work in the host lab examining the functional role of Dicer and DGCR8 in glial development.
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