Rett syndrome (RTT) is an X-linked dominant disorder caused by loss-of-function mutations in the geneencoding methyl CpG binding protein 2 (MECP2). Studies of human patient samples and animal modelssuggest that MECP2/MeCP2 may play essential roles In neuronal maturation and synapseformation/maintenance during development. The neurobiology of MeCP2 in neuronal development remainsto be fully characterized, in the dentate gynjs of the hippocampus, new granule neurons are continuouslygenerated from neural progenitors throughout life in all mammals examined, including humans. Adulthippocampal neurogenesis is dynamically regulated by physiological and pathological stimuli and believed tobe involved in specific brain functions, such as leaming and memory. Defect in adult neurogenesis has alsobeen implicated in certain brain disorders. Adult neurogenesis recapitulates the complete neuronaldevelopmental process in a mature brain environment, including proliferation and fate specification of neuralprogenitors, neuronal morphogenesis, migration, axon and dendritic development, and synapsedevelopment by neuronal progeny. Our recent studies and others showed that neuronal development in theadult brain follows a stereotypic pattern in reaching same milestones as in embryonic neurogenesis, yet theintegration process for adult-born neuron is significantly prolonged. Such a stereotypic and prolongeddevelopment process for a single neuronal subtype (dentate granule cell) in a relative 'steady-state' ofmature brain offers a unique model system to investigate mechanisms of neuronal development in vivo in agreat detail. We have developed a 'single-cell genetic' approach for studying the development of newborngranule cells in vivo using a combination of immunocytochemistry, multi-photon confocal microscopy,electron microscopy and electrophysiology. In the cun-ent project, we aim to examine the role and underiyingmechanisms of MeCP2 in postnatal hippocampal neurogenesis in vivo with the following hypothesis: MeCP2regulates the formation, maturation and maintenance of GABAergic and glutamatergic synapses ofnew neurons in the adult brain. Our project, addressing in great detail the cell autonomous roles of MeCP2in vivo, will contribute from a unique aspect to the main goal of the whole center in understanding themolecular basis of RTT. Findings from these studies will be cross-compared with those from the olfactorysystem (Project 2) to elucidate similarities and differences of neuronal functions of MeCP2 in differentdevelopmental stages and brain regions. Random X-inactivation of MECP2 occurs in female and even thosewith favorable skewing of X inactivation and predominant expression of the WT MECP2 allele exhibitlearning disability. Our model system examining individual neurons with MeCP2 dysfuncl^tion in a normalneuronal environment thus have significant clinical implications for the pathophysiology and etiology of RTT. n addition, RTT normally manifests at 6-18 months of age well beyond the primary neurogenesis, ourstudies of functional roles of MeCP2 in postnatal neurogenesis may thus provide additional novel insights.More importantly, such in vivo system provides a platform for exploring pharmacological and behavioraltherapeutic approaches that can be eventually applied in humans to overcome such brain disorder (Project1), the ultimate goal of the center.

Public Health Relevance

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD069184-02
Application #
8149808
Study Section
Special Emphasis Panel (ZHD1-MRG-C (NS))
Program Officer
Oster-Granite, Mary Lou
Project Start
2010-09-30
Project End
2013-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
2
Fiscal Year
2011
Total Cost
$244,226
Indirect Cost
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Su, Yijing; Shin, Jaehoon; Zhong, Chun et al. (2017) Neuronal activity modifies the chromatin accessibility landscape in the adult brain. Nat Neurosci 20:476-483
Song, Juan; Olsen, Reid H J; Sun, Jiaqi et al. (2016) Neuronal Circuitry Mechanisms Regulating Adult Mammalian Neurogenesis. Cold Spring Harb Perspect Biol 8:
Bonaguidi, Michael A; Stadel, Ryan P; Berg, Daniel A et al. (2016) Diversity of Neural Precursors in the Adult Mammalian Brain. Cold Spring Harb Perspect Biol 8:a018838
Ming, Guo-Li; Tang, Hengli; Song, Hongjun (2016) Advances in Zika Virus Research: Stem Cell Models, Challenges, and Opportunities. Cell Stem Cell 19:690-702
Shin, Jaehoon; Ming, Guo-Li; Song, Hongjun (2015) Molecular toggle switch of histone demethylase LSD1. Mol Cell 57:949-950
Griesi-Oliveira, K; Acab, A; Gupta, A R et al. (2015) Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons. Mol Psychiatry 20:1350-65
Shin, Jaehoon; Ming, Guo-li; Song, Hongjun (2015) Seeking a roadmap toward neuroepigenetics. Neuron 86:12-5
Ma, Dongliang; Yoon, Su-In; Yang, Chih-Hao et al. (2015) Rescue of Methyl-CpG Binding Protein 2 Dysfunction-induced Defects in Newborn Neurons by Pentobarbital. Neurotherapeutics 12:477-90
Huang, Wei; Ming, Guo-Li; Song, Hongjun (2015) Experience matters: enrichment remodels synaptic inputs to adult-born neurons. Neuron 85:659-61
Ming, Guo-li (2015) Neuroepigenetics: Introduction to the special issue on epigenetics in neurodevelopment and neurological diseases. Exp Neurol 268:1-2

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