Rett syndrome is a neurodevelopmental disorder caused by mutations in the methyl CpG binding protein 2 gene (Mecp2). Loss of Mecp2 function results in defects in neuronal maturation, synaptogenesis and dendritic development in the central nervous system. MeCP2 is a transcription regulator that binds preferentially to methylated CpG dinucleotides sequences. Identification of MeCP2 target genes and understanding their functions in the establishment of functional circuitry is critical for future development of therapeutic approaches. Several unique characteristics make the vertebrate olfactory system an excellent model to study MeCP2 function. 1). Olfactory sensory neurons are the sole neuronal type in the olfactory epithelium. This will facilitate the identification of transcription regulations without the interference of mixed regulatory effects that are seen in mixed neuronal populations of cortical tissue. 2) The intricate and precise olfactory connections allow identification of axon mistargeting out of their specific olfactory bulb foci. 3) Manipulation of neuronal activity at the physiological level can be easily achieved due to the accessibility of olfactory sensory neurons in the nasal cavity. The goal of this study is to use the olfactory system as a model to further define MeCP2 function in circuitry formation and refinement.
In Aim 1, we will test the hypothesis that MeCP2 is required for the formation of precise adult olfactory connections.
In Aim 2, we will test the hypothesis that MeCP2 regulates expression of cell adhesion molecules in olfactory sensory neurons.
In Aim 3, we will test the hypothesis that MeCP2 tunes transcription of activity-regulated cell adhesion molecules in the olfactory system. Through this study, we hope to gain better understanding of MeCP2 function not only in the olfactory system but also in other regions of the central nervous system.

Public Health Relevance

This study aims to identify target genes of MeCP2 and investigate MeCP2 function using the mouse olfactory system as a model. Understanding MeCP2 function in the formation of olfactory connections will not only contribute to our basic understanding of brain development but also provide insights toward the design of interventions for Rett syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC011346-04
Application #
8580200
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Sullivan, Susan L
Project Start
2010-12-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
4
Fiscal Year
2014
Total Cost
$293,569
Indirect Cost
$102,319
Name
University of California Davis
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Lee, Wooje; Yun, Jung-Mi; Woods, Rima et al. (2014) MeCP2 regulates activity-dependent transcriptional responses in olfactory sensory neurons. Hum Mol Genet 23:6366-74