Inherited neuropathies are among the most common human genetic diseases. These syndromes are characterized by severe motor and sensory deficits secondary to abnormal nerve myelination resulting in significant patient morbidity and mortality. The underlying genetic defects of these neuropathies occur primarily in genes encoding the myelin structural proteins MPZ, PMP-22 and connexin-32. Recently, however, mutations in the transcription factor Egr2 have also been associated with these syndromes. The connection between Egr2 and these syndromes was made after peripheral nerves in Egr2-deficient mice appeared poorly myelinated due to a Schwann cell differentiation arrest at the promyelinating stage. Together, these results strongly suggest that Egr2 is a crucial regulator of a differentiation program, which culminates in the myelinating Schwann cell phenotype. In this proposal, we outline experiments aimed at understanding the molecular mechanisms by which Egr2 regulates the myelination process. Gain-of-function experiments using adenovirus infection of Schwann cells will be utilized to perform Egr2 target gene profiling via microarray screening. Egr2 mutants associated with inherited neuropathies will be characterized in in vitro myelination assays and tested for their ability to activate expression of Egr2 target genes. In addition, one of the neuropathy-associated Egr2 mutations is located in the domain that interacts with the Nab proteins, modulators of Egr2 activity. We will therefore investigate the role of the Nab proteins in regulating myelination. The presence of mutations in the Nabl or Nab2 genes will be sought in patients with inherited neuropathy. Finally, gene targeting will be used to produce mice that harbor neuropathy-associated Egr2 mutations in order to create mouse models of these inherited neuropathies. The peripheral nervous system of these mice will be examined for deficits in Schwann cell differentiation and peripheral nerve myelination. The expression of Egr2-regulated genes will be examined in nerves of these mutant mice. These studies will provide new insight into how mutations in Egr2 lead to peripheral neuropathies, information that may lead to novel therapies for these diseases.
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