Autism is a neurodevelopmental disorder that develops in the first three years of life. It is probably caused by diverse genetic mutations that remain to be identified. Rett syndrome is a devastating form of autism spectrum disorders, and it is one of the few in which the underlying genetic cause, mutations on the MeCP2 gene, has been identified. MECP2 is a methyl-DNA binding protein that is thought to function as a transcriptional repressor. Despite immense efforts, only a few genes have been shown to be regulated by MECP2 in vivo. Here, we report that MECP2 regulates olfactory receptor expression, in an unusual way. In MeCP2 knockout mice olfactory receptor neurons express multiple olfactory receptors, in contrast to the wild type mice where only one olfactory receptor allele is expressed in each neuron. Interestingly, the olfactory receptor alleles that appear coexpressed in the MeCP2 knockout neurons are always members of the same chromosomal cluster. This observation suggests that MeCP2 functions as an insulator that could be regulating the monogenic expression of gene families that are organized in chromosomal clusters like the olfactory receptor genes. The violation of the "one receptor per neuron" rule provides a robust molecular assay for MeCP2 activity. We propose to use this assay in a high throughput screen of chemicals that can reverse the molecular consequences of MeCP2 deletion in dissociated olfactory neurons. These compounds could eventually be the basis for a pharmacological treatment of Rett syndrome symptoms.

Public Health Relevance

This application proposes the use of a robust molecular phenotype that we discovered in MeCP2 knockout olfactory neurons, for a high throughput screen for compounds that restore the deficiencies caused by MeCP2 deletion. MeCP2 mutations are the main cause of Rett syndrome;therefore our application has significant relevance to the health and quality of life of Rett syndrome patients and their families.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH091661-03
Application #
8306864
Study Section
Special Emphasis Panel (ZNS1-SRB-B (21))
Program Officer
Driscoll, Jamie
Project Start
2010-08-17
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$290,087
Indirect Cost
$92,087
Name
University of California San Francisco
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Colquitt, Bradley M; Markenscoff-Papadimitriou, Eirene; DuffiƩ, Rachel et al. (2014) Dnmt3a regulates global gene expression in olfactory sensory neurons and enables odorant-induced transcription. Neuron 83:823-38
Colquitt, Bradley M; Allen, William E; Barnea, Gilad et al. (2013) Alteration of genic 5-hydroxymethylcytosine patterning in olfactory neurons correlates with changes in gene expression and cell identity. Proc Natl Acad Sci U S A 110:14682-7
Magklara, Angeliki; Lomvardas, Stavros (2013) Stochastic gene expression in mammals: lessons from olfaction. Trends Cell Biol 23:449-56