Rett syndrome [RTT, MIM 312750] is an X-linked postnatal developmental disorder characterized by loss of acquired skills, impairment of cognitive and motor functions, autonomic dysfunction, ataxia, tremors, seizures, autistic features, and stereotypic hand movements. RTT is caused by mutations in the X-linked MECP2 gene which encodes methyl-CpG-binding protein 2 (MeCP2). MeCP2 is thought to be a transcriptional repressor that links DNA methylation to chromatin modifications. Recently, we also found that MeCP2 interacts with an RNA-binding protein and can affect RNA splicing. We and others have shown that mutations in MECP2 cause a broad spectrum of disorders that display partial features of RTT such as autism, mild mental retardation, movement abnormalities, or seizures. Favorable X-chromosome-inactivation patterns in some of these patients and in partially symptomatic female mice that model RTT led us to propose that the diverse phenotypes of classic RTT result from MeCP2 dysfunction in a particular subset of neurons. Furthermore, we propose that loss of function of MeCP2 in specific neurons causes gene expression and RNA splicing changes that mediate the neuron-specific phenotypes. Lastly, we propose that pharmacologic therapies that target some of the neuron-specific changes linked to distinct phenotypes are likely to modulate some of these RTT phenotypes.
The Specific Aims of this project are: (1) To identify the neuroanatomical bases of several key features of RTT by deleting Mecp2 in distinct neuronal populations -- using Cre/LoxP technology-- and characterizing the phenotypes of the conditional mutant mice. (2) To identify MeCP2 targets by evaluating neuron-specific gene expression and splicing pattern changes in Mecp 308/y mice which reproduce RTT phenotypes;we will use a novel approach that employs neuron- specific BACarray lines and new splicing/expression arrays. (3) To conduct preclinical pharmacologic trials targeted at clinically relevant molecular changes (based on Data from Aims 1 and 2) to determine if such therapies will alter the RTT disease course. As a proof of concept, we will use drugs that modulate CRH and AVP activities given our discovery of the potential roles of these two MeCP2 targets in RTT phenotypes. These studies will provide insight about the neuronal subtypes and neurotransmitter systems that mediate certain key features of RTT and related disorders such as autism and X-linked mental retardation. They will also provide the community with a rich resource of neuron-specific gene expression/splicing patterns and how some of these patterns differ in RTT. Last but not least, the data generated under this study have the potential to identify effective pharmacologic interventions that could benefit RTT patients.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Developmental Brain Disorders Study Section (DBD)
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Mamounas, Laura
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Baylor College of Medicine
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Lombardi, Laura M; Zaghlula, Manar; Sztainberg, Yehezkel et al. (2017) An RNA interference screen identifies druggable regulators of MeCP2 stability. Sci Transl Med 9:
Lu, Hui; Ash, Ryan T; He, Lingjie et al. (2016) Loss and Gain of MeCP2 Cause Similar Hippocampal Circuit Dysfunction that Is Rescued by Deep Brain Stimulation in a Rett Syndrome Mouse Model. Neuron 91:739-747
Zoghbi, Huda Y; Beaudet, Arthur L (2016) Epigenetics and Human Disease. Cold Spring Harb Perspect Biol 8:a019497
Sztainberg, Yehezkel; Zoghbi, Huda Y (2016) Lessons learned from studying syndromic autism spectrum disorders. Nat Neurosci 19:1408-1417
Ure, Kerstin; Lu, Hui; Wang, Wei et al. (2016) Restoration of Mecp2 expression in GABAergic neurons is sufficient to rescue multiple disease features in a mouse model of Rett syndrome. Elife 5:
Meng, Xiangling; Wang, Wei; Lu, Hui et al. (2016) Manipulations of MeCP2 in glutamatergic neurons highlight their contributions to Rett and other neurological disorders. Elife 5:
Ito-Ishida, Aya; Ure, Kerstin; Chen, Hongmei et al. (2015) Loss of MeCP2 in Parvalbumin-and Somatostatin-Expressing Neurons in Mice Leads to Distinct Rett Syndrome-like Phenotypes. Neuron 88:651-8
Lombardi, Laura Marie; Baker, Steven Andrew; Zoghbi, Huda Yahya (2015) MECP2 disorders: from the clinic to mice and back. J Clin Invest 125:2914-23
Baker, Steven Andrew; Lombardi, Laura Marie; Zoghbi, Huda Yahya (2015) Karyopherin ? 3 and karyopherin ? 4 proteins mediate the nuclear import of methyl-CpG binding protein 2. J Biol Chem 290:22485-93
Chen, Lin; Chen, Kaifu; Lavery, Laura A et al. (2015) MeCP2 binds to non-CG methylated DNA as neurons mature, influencing transcription and the timing of onset for Rett syndrome. Proc Natl Acad Sci U S A 112:5509-14

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