Folic Acid and Rett Syndrome: Understanding DNA Methylation-Dependent Gene Expression in Neurons regulating body growth and metabolism
Folic acid plays a key role in the prevention of neural tube defects and is required for methylation of DNA and other intracellular substrates. Rett syndrome (RTT) is an X-linked disorder caused by loss of function mutations in the gene encoding methyl-CpG binding protein 2 (MeCP2), a DNA methylation-dependent transcriptional repressor which may also regulate RNA splicing.
RTT manifests with growth abnormalities, developmental delay and autistic features, and genetic data suggest that its clinical features stem from impairment of specific brain regions. However, the precise neuronal subtypes affected by the disease, the genetic targets of Mecp2 in vivo or the molecular events resulting from its dysfunction remain largely unknown. Of a handful of Mecp2-dependent transcriptional changes identified to date, none have been directly linked to a specific disease phenotype.
The specific aims are to:
- Characterize the phenotype and gene expression abnormalities of mice with Mecp2 mutation restricted to Agrp/Npy or Pomc1 neurons of the arcuate nucleus.
- Demonstrate that reduction of Agrp and Npy overexpression normalizes growth and metabolic dysfunction, but not other neurological abnormalities in Mecp2 mutant mice; conversely, reduction of Pomc1 overexpression worsens these growth abnormalities.
- Genetically dissect the role of Npy and Pomc1 on growth and hypothalamic gene expression in Mecp2 mutant mice treated with different levels of dietary methyl donors.
Focusing on a clinically relevant manifestation of RTT, these studies will begin to shed light on Mecp2-dependent cellular and molecular abnormalities and the role of methyl donors in hypothalamic function. Furthermore, proving the validity of the hypotheses at the basis of this proposal will provide a solid basis for the search of hypothalamic abnormalities in human patients with RTT and a foundation to the pursuit of rational treatment strategies.
Relevance of the project to IDDRC mission:
Our project has direct relevance to the mission of the IDDRC. Several neurological diseases including autism, mental retardation and neurodegenerative disorders are clearly complex and heterogeneous and have both genetic and environmental causes.
Our studies aim to identify disease pathways in the brain that are sensitive to environmental manipulations of the epigenome, and to dissect the mechanisms of these effects. We believe that these studies could lead to either preventative or therapeutic manipulations in a number of neurological disorders with primary or secondary abnormalities of epigenetic regulation.