Charcot Marie Tooth disease (CMT), in all its forms, is the most common inherited peripheral neuropathy often characterized by severe demyelination in the peripheral nervous system. In some cases it is caused by aberrant programs controlling Schwann Cell (SC) development, whereas in other cases, SC development is unimpaired but improper myelin maintenance results in late-onset neuropathy. Thus, to understand the pathomechanisms of this disease warrants a better grasp of the molecular programs underlying Schwann cell development as well as myelin maintenance. MicroRNAs, are a class of small, naturally occurring, regulatory RNAs that bind in a sequence specific manner to their cognate targets mRNAs, thereby reducing translation efficiency as well as steady state mRNA levels. These newly discovered molecules are postulated to target almost 30% of all mRNAs, and are thus likely to be involved in various stages of SC development as well as in myelin maintenance. Here we will first determine the global function of microRNAs in SC development and in myelin maintenance by eliminating the key microRNA processing enzyme, dicer. Next we will elucidate the specific microRNAs that may target mRNAs of key developmental regulators or key myelin structural proteins. These studies will open exciting possibilities for microRNA-mediated manipulations of SC gene expression as therapeutic avenues for CMT. The role of microRNAs in peripheral myelin formation and maintenance
The proposed studies will detail the role of microRNAs as critical regulators of genes expressed in the Schwann cell lineage, and thus will have important implications for understanding the pathomechanisms of Charcot Marie Tooth Disease, and possible therapeutics.
| He, Xuelian; Yu, Yang; Awatramani, Rajeshwar et al. (2012) Unwrapping myelination by microRNAs. Neuroscientist 18:45-55 |
| Yun, Beth; Anderegg, Angela; Menichella, Daniela et al. (2010) MicroRNA-deficient Schwann cells display congenital hypomyelination. J Neurosci 30:7722-8 |
