In this case also, the result is substantial reduction in regeneration. We find that enforced c-Jun expression in injured Wlds nerves is sufficient to restore axonal regeneration rates to WT values, lending significant support to our model. It is important to note that although the Bungner cells generated in the mutants are dysfunctional, other Schwann cell functions are normal. Thus, mutant cells remyelinated those axons that regenerated, Schwann cell development appeared normal, and Schwann cells and nerve function in uninjured adults were normal. Although 172 genes were disregulated in the distal stump of the c-Jun mutants, the large majority

of the ∼4,000 genes regulated in injured WT nerves remained normally regulated. Therefore, the absence of c-Jun does not have a general impact on the Schwann cell phenotype. Instead, c-Jun appears selleck chemicals to have a specific function in adult cells, where it is required for activation of the repair program and timely suppression of the myelin program. The Schwann cell response to injury is commonly referred to as dedifferentiation, implying that adult denervated cells revert

to an earlier stage resembling the immature Schwann cells of perinatal nerves (Harrisingh et al., 2004; Jessen and Mirsky, 2005; Chen et al., 2007; Woodhoo et al., 2009). It is becoming clear, however, that this view is incomplete. These cells have a different structure, molecular profile, and function. Therefore, the immature cells, generated BMS-354825 molecular weight from Schwann cell precursors

during development, and Bungner cells generated in response to adult nerve injury, represent two distinct differentiation states. In injured nerves, myelinating Schwann cells, that are specialized to support fast conduction of action potentials, transform to Bungner cells that are specialized for the unrelated task of organizing nerve repair. This represents an unambiguous change of function, brought about by the combination of dedifferentiation and activation of an alternative differentiation program, the c-Jun Metalloexopeptidase dependent Schwann cell repair program. Transitions that share this set of features have been described in other systems, where they are generally referred to as transdifferentiation (Jopling et al., 2011). The regeneration defects in the c-Jun mutant are substantially more severe than those reported for other mouse mutants, in spite of the fact that the genetic defect is restricted to Schwann cells. The likely reason is the number and diversity of the molecules controlled by this single transcription factor. Among the 172 molecules that are abnormally expressed in the mutant are growth factors, adhesion molecules, growth-associated proteins, and transcription factors. This allows c-Jun to integrate a broad collection of functions that support nerve regeneration, and therefore to act as a global regulator of the Schwann cell repair program.