Rett Syndrome (RTT) is a dominant X-linked neurodevelopment disorder caused by mutation of Methyl- CpG-binding Protein 2 (MECP2). Affected patients have a variety of autonomic abnormalities that adversely affect quality of life for these individuals and likely contribute to the sub-population of RTT patients prone to sudden unexpected death. Male mice that completely lack MeCP2 function (Mecp2null/Y) reproduce many features of RTT including breathing abnormalities and constipation. Removing MeCP2 function from neural crest derivatives in the Wnt-1 expression domain reproduces the lethality observed in Mecp2null/Y mice. The hypothesis of this proposal is that dismption of MeCP2 function in the Wnt-1 domain causes autonomic dysfunction which ultimately leads to early death. To address the role of neural crest derived tissue in autonomic dysfunction during RTT pathogenesis, I plan the following experiments. I will perform detailed characterization of both the autonomic function in these animals as well as the cellular composition of the neural crest derivatives, with particular focus on the sympathetic ganglia. Additionally, I will use genetic techniques to introduce MeCP2 function in the neural crest of animals that otherwise lack MeCP2 function and determine if this is sufficient to restore normal lifespan and autonomic function. The research outlined in this proposal seeks to understand the causes of both the autonomic dysfunction as well as the early lethality observed in Mecp2null/Y mice. Ultimately, this understanding will help both develop therapeutic options for girls with RTT as well as provide insight into the neural mechanisms of autonomic control.
