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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS066601-02
Application #
7903905
Study Section
Special Emphasis Panel (ZRG1-F01-E (20))
Program Officer
Mamounas, Laura
Project Start
2009-08-01
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
2
Fiscal Year
2010
Total Cost
$34,956
Indirect Cost
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Ward, Christopher S; Huang, Teng-Wei; Herrera, José A et al. (2016) Loss of MeCP2 Causes Urological Dysfunction and Contributes to Death by Kidney Failure in Mouse Models of Rett Syndrome. PLoS One 11:e0165550
Ramirez, Jan-Marino; Ward, Christopher Scott; Neul, Jeffrey Lorenz (2013) Breathing challenges in Rett syndrome: lessons learned from humans and animal models. Respir Physiol Neurobiol 189:280-7
Pitcher, Meagan R; Ward, Christopher S; Arvide, E Melissa et al. (2013) Insulinotropic treatments exacerbate metabolic syndrome in mice lacking MeCP2 function. Hum Mol Genet 22:2626-33
Samaco, Rodney C; McGraw, Christopher M; Ward, Christopher S et al. (2013) Female Mecp2(+/-) mice display robust behavioral deficits on two different genetic backgrounds providing a framework for pre-clinical studies. Hum Mol Genet 22:96-109
Huang, Wei-Hsiang; Tupal, Srinivasan; Huang, Teng-Wei et al. (2012) Atoh1 governs the migration of postmitotic neurons that shape respiratory effectiveness at birth and chemoresponsiveness in adulthood. Neuron 75:799-809
McCauley, Mark D; Wang, Tiannan; Mike, Elise et al. (2011) Pathogenesis of lethal cardiac arrhythmias in Mecp2 mutant mice: implication for therapy in Rett syndrome. Sci Transl Med 3:113ra125
Ward, Christopher S; Arvide, E Melissa; Huang, Teng-Wei et al. (2011) MeCP2 is critical within HoxB1-derived tissues of mice for normal lifespan. J Neurosci 31:10359-70