Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder caused by mutations in MECP2, which encodes the transcriptional repressor methyl-CpG binding protein 2 (MeCP2).  It is characterized by a period of apparent normal development followed by loss of acquired skills and the onset of autistic features.  Efforts have focused on identifying MeCP2 target genes, yet relatively few MeCP2 targets of confirmed biological relevance to RTT pathogenesis have been identified.  Also, in spite of evidence linking the preferential CNS MeCP2 expression pattern to RTT features, the various neuronal subtypes responsible for specific RTT phenotypes remain to be elucidated.  Strong evidence supports a role for the serotonergic system in the etiology of anxiety and anxiety-related social withdrawal.  Pathological defects associated with this system have also been demonstrated in RTT.  Thus, the hypothesis of my work is that MeCP2 plays a key modulatory role in the serotonergic system; the loss of MeCP2 function in this system may cause anxiety and social behavior phenotypes of RTT that can be attributed to alterations in serotonergic neuron gene expression.
The Specific Aims of my work are: (1) To analyze the behavioral consequences of MeCP2 deficiency in serotonergic neurons. (2) To identify serotonergic neuron gene expression alterations that are responsible for a subset of phenotypes in Mecp2-mutant mice using a novel approach termed “BACarray” technology.  (3) To validate and investigate candidate MeCP2 targets using quantitative reverse transcriptase-PCR and chromatin immunoprecipitation.
RTT is a devastating neurological disorder and there are no effective therapies for the vast majority of its features.  The experiments outlined in this proposal will provide insight into the molecular role of one particular neuronal subtype (serotonergic neurons) in mediating a subset of RTT phenotypes.  Behavioral impairments such as heightened anxiety and social behavior deficits that are observed in RTT might result from the absence of MeCP2 in the serotonergic system.  Alternatively, other phenotypes such as breathing dysrhythmia may be attributed to this system.  By complementing our behavioral studies with the investigation of MeCP2 target genes in a cell-specific manner, novel MeCP2 target genes relevant to the manifestation of phenotype(s) observed in RTT will be revealed.  This would be the first step for identifying potential molecular changes that could be targeted therapeutically.  Defining the fundamental neuronal and molecular changes of some features of RTT has far-reaching benefits, given the mounting evidence that MECP2 mutations are involved in a growing list of neuropsychiatric disorders.