Modeling Mecp2 Mutations and Potential Therapies Using the Olfactory System

ALICIA DEGANO; AMY PALMER; GABRIELE RONNETT

LAnsdowne Resort & Spa-Leesburg, VA

Simposio; 11th Annual Rett Syndrome Symposium; 2010

International Rett Syndrome Foundation

>A serious limitation to understanding the molecular pathophysiology of many brain diseases is the inaccessibility of brain tissue to examination during active phases of the disease progression. This is especially true in developmental brain disorders. The olfactory system has several attributes, including a simple organization and ongoing neurogenesis, which make it attractive for modeling neuronal development and CNS diseases. Our studies demonstrate the feasibility of this approach. Here, we describe our results on Rett Syndrome (RTT). RTT is caused by mutation in methyl-CpG binding protein 2 (MeCP2), which is a member of a family of transcriptional factors that binds methyl-CpG DNA base pairs. Although a cause for RTT is established, little is known about the specific neurodevelopmental defects that underlie its complex clinical course.  Understanding the consequences of MeCP2 mutation has been daunting, due to the complexity of the CNS and the large number of genes potentially affected. We provided evidence for a specific neuronal defect that results from MeCP2 mutation.  We have used mouse models of MeCP2 mutation, the olfactory system, and human olfactory nasal biopsies to demonstrate that (1) MeCP2 is expressed with neuronal differentiation, (2) MeCP2 mutation mimics the clinical course of RTT, causing two distinct phases of compromised neuronal function, (3) developmentally, MeCP2 mutation transiently disrupts neuronal terminal differentiation, axonal targeting, and synaptogenesis, (4) long-term, MeCP2 mutation affects synaptic organization and function, and (5) MeCP2 mutation causes dynamic temporal and regional changes in the expression of specific functional protein groups.Our studies of the olfactory system revealed similarities between the neurodevelopmental defects found in RTT and mouse models of MeCP2 mutation, validating the olfactory system as a model.We now address the mechanisms that underlie these findings. Our recent data indicate that MeCP2 mutation affects several signaling pathways to cause a non-cell autonomous defect in synaptogenesis. These findings have broad implications for developmental disorders and their potential therapies.