From a historical perspective, the most common inherited neuropathies were divided into two forms of Charcot-Marie-Tooth disease, largely on the basis of electrophysiology: type1, which primarily affects myelin, and type2, which primarily affects axons. Common forms of type1 are caused by dominant mutations of genes for compact myelin proteins, PMP-22 in type1A and P0 in type1B. Molecular mechanisms by which pathological genes express their action remain largely unknown. Functions involved in maintaining intact myelin sheaths in adulthood might be altered in pathological mutations.

A new work conducted by Charnay and colleagues show that the transcription factor KROX20, known to be involved in the onset of myelination, is also integral to its maintenance (Decker L., et al., Peripheral myelin maintenance is a dynamic process requiring constant Krox20 expression. J. Neurosci. 26, 9771-9779, 2006).

A role for KROX20 in preserving myelin integrity was suggested by its expression throughout adulthood in Schwann cells and by links between mutations in its gene and congenital and late-onset human myelinopathies. Previously generated Krox20 mutant mice died at early perinatal stages and could not provide answers about myelin maintenance during adulthood. The researchers therefore developed two conditional mouse mutants (in one mouse model mutation was inducibile at a specific time-point by tamoxifen treatment) that evade early lethality by delaying the onset of Krox20 inactivation.

In response to Krox20 inactivation, mature Schwann cells seemed to return to an immature state, indicated by the upregulation of markers of immaturity, such as Sox2, and made ineffective attempts to initiate re-myelination.

This study shows that KROX20 is crucial for myelin maintenance, and introduces two models of delayed Krox20 inactivation; in particular the inducibile mutant replicates many features of Charcot-Marie-Tooth disease, revealing a close link between late onset of Krox20 mutation effects and this devastating pathology.


BM&L-November 2006