(Taken from Abstract): Myelination is one of the fundamental adaptations of the vertebrate nervous system, and its normal functioning is essential for health. Genetic manipulation of mice has revealed that two, unrelated transcription factors, SCIP (also known as tst-1 or Oct-6) and Krox-20, are essential for myelination in the peripheral nervous system. These transcription factors are expressed by Schwann cells, and myelinating Schwann cells do not develop normally in mice that are genetically null for either SCIP or Krox-20. In both SCIP and Krox-20-null mice, the development of myelinating Schwann cells appears to be arrested at the promyelinating stage, when myelinating Schwann cells have ensheathed axons in a 1:1 manner but have not yet elaborated a myelin sheath. In SCIP-null mice, Schwann cells are transiently arrested at this stage, whereas in Krox-20-null mice, Schwann cells are permanently arrested at the promyelinating stage. It is unclear how the lack of either SCIP or Krox-20 results in dysmyelination. The observation that SCIP and Krox-20 both appear to be expressed at relatively high levels in promyelinating Schwann cells, which is exactly when the development of myelinating Schwann cells is arrested in null mice, leads them to hypothesize that these two transcription factors interact in promyelinating Schwann cells to regulate the expression of genes that are essential for the formation of the myelin sheath. In this grant, the principal investigator will evaluate various aspects of this hypothesis, by determining (1) at what stage Schwann cells express SCIP, (2) whether SCIP and Krox-20 interact in the regulation of Schwann cell development, (3) the effects of SCIP and Krox-20 on the phenotype of Schwann cells in vitro, and (4) the target genes of SCIP and Krox-20.
