Loss-of-function mutations or duplication in methyl-CpG binding protein 2 (MECP2) cause two severe neurodevelopmental disorders: Rett syndrome and MECP2 duplication syndrome, respectively. While the genetic cause of these disorders is known, the mechanism by which disruption in MECP2 leads to pathogenesis is unknown; this has prevented the development of targeted therapies. Treatment with secreted factors has shown some efficacy in preclinical mouse models of MECP2-disorders. To identify candidate secreted factors misregulated by MeCP2, transcriptome profiles collected from Mecp2-null mouse models were evaluated, and Growth differentiation factor 11 (GDF11) was identified as a growth factor sensitive to MECP2-levels. GDF11 is downregulated in Mecp2-null models, while upregulated in MECP2-transgenic models. The opposing regulation of GDF11 by MECP2 implicates GDF11 misregulation as one potential shared mechanism between Rett and MECP2 duplication syndromes. GDF11 is a transforming growth factor beta family ligand that is a critical patterning morphogen for the skeletal system. However, despite broad expression throughout the brain, the role of GDF11 in brain development is unknown. The work proposed in this fellowship will test the hypothesis that GDF11 is a key morphogen for brain development, and that its misregulation in models of MECP2-disorders contributes to MECP2-disorder phenotypes. This hypothesis will be tested through the following specific aims: 1. Test if modulating brain specific dose of GDF11 by viral or genetic methods itself causes aberrant neurological phenotypes. 2. Test if normalization of GDF11 levels rescues neurological phenotypes seen in mouse models of MECP2- disorders. 3. Test the regulatory relationship between MECP2 and GDF11 by modeling the temporal changes in the transcriptome after perturbation of MECP2-levels to identify primary gene expression changes. The results from this fellowship will address three key questions in the field: 1) is GDF11 dose important in brain development, 2) does rescue of GDF11-levels ameliorate phenotypes in mouse models of MECP2-disorders, and 3) what are the primary gene expression changes that occur upon modulation of MECP2 levels.
Mutations or duplication of methyl-CpG binding protein 2 (MECP2) cause two severe neurological disorders, Rett syndrome and MECP2 duplication syndrome respectively. Growth differentiation factor 11 (GDF11) is a secreted protein misregulated in both Rett syndrome and MECP2 duplication syndrome mouse models. This proposal will test the role of GDF11 in brain development and test if correcting GDF11 levels is a viable therapeutic strategy for MECP2-related disorders.
