Krox-20 controls SCIP expression, cell cycle exit and susceptibility to apoptosis in developing myelinating Schwann cells

Abstract

The transcription factors Krox-20 and SCIP each play important roles in the differentiation of Schwann cells. However, the genes encoding these two proteins exhibit distinct time courses of expression and yield distinct cellular phenotypes upon mutation. SCIP is expressed prior to the initial appearance of Krox-20, and is transient in both the myelinating and non-myelinating Schwann cell lineages; while in contrast, Krox-20 appears approximately 24 hours after SCIP and then only within the myelinating lineage, where its expression is stably maintained into adulthood. Similarly, differentiation of SCIP−/− Schwann cells appears to transiently stall at the promyelinating stage that precedes myelination, whereas Krox-20(−/−) cells are, by morphological criteria, arrested at this stage. These observations led us to examine SCIP regulation and Schwann cell phenotype in Krox-20 mouse mutants. We find that in Krox-20(−/−) Schwann cells, SCIP expression is converted from transient to sustained. We further observe that both Schwann cell proliferation and apoptosis, which are normal features of SCIP+ cells, are also markedly increased late in postnatal development in Krox-20 mutants relative to wild type, and that the levels of cell division and apoptosis are balanced to yield a stable number of Schwann cells within peripheral nerves. These data demonstrate that the loss of Krox-20 in myelinating Schwann cells arrests differentiation at the promyelinating stage, as assessed by SCIP expression, mitotic activity and susceptibility to apoptosis.