Oligodendrocytes are myelin-forming macroglia found in all regions of the central nervous system. The major function of myelin sheaths is to ensure the rapid and faithful transmission of electrical signals. During development, oligodendrocytes precursor cells (OPCs) have to go through a series of morphological and molecular changes before they become fully differentiated into mature myelinating oligodendrocytes. The differentiation and myelination processes of oligodendrocytes are regulated by protein tyrosine phosphorylation. Recently we found that Ick cytoplasmic serine/threonine kinase is selectively up-regulated in differentiating OPCs and disruption of Ick resulted a significant inhibition of OL differentiation. In this application, we hypothesize that Ick enhances OPC differentiation and axonal myelination by Ick during development and enhance myelin repair following demyelination insults.
The first aim of this application is to examine whether Ick expression is required for myelin development in Ick conditional mutant mice, and induced expression of Ick protein in OPCs promotes developmental myelination in inducible transgenic mice. In the second aim, we will test the hypothesis that Ick expression is also required for axonal remyelination in adult animals and overexpression of Ick in inducible transgenic mice can promote myelin recovery following demyelination This line of study could help us understand molecular mechanisms that control axonal myelination process and provide insights into the development of molecular approaches to stimulate oligodendrocyte regeneration and remyelination in demyelinating diseases.
The proposed studies will provide important information on the functional role of Ick cytoplasmic serine/threonine kinase in the control of oligodendrocyte differentiation, myelin development and repair in the developing central nervous system. Knowledge obtained from this study will yield important insights into the development of molecular strategies for promoting oligodendrocyte regeneration and axonal remyelination in neurological patients and spinal cord injury patients.
