Isoform-Specific Toxicity of Mecp2 in Postmitotic Neurons: Suppression of Neurotoxicity by FoxG1

• DOI: 10.1523/jneurosci.5841-11.2012
• Publication Date: 2012-02-22T17:51:40Z
• Authors: Somasish Ghosh Da...; Farah H. Bardai; Chi Ma; Valerie Price; Varun Rawat; Pragya Verma; Vinodh Narayanan; Santosh R. D'Mello
• Keywords: MeCP2; Neurotoxicity; Rett Syndrome

The methyl-CpG binding protein 2 (MeCP2) is a widely expressed protein, the mutations of which cause Rett syndrome. level MeCP2 highest in brain where it selectively mature neurons. Its functions postmitotic neurons are not known. gene alternatively spliced to generate two proteins with different N termini, designated as MeCP2-e1 and MeCP2-e2 . physiological significance these isoforms has been elucidated, generally assumed they functionally equivalent. We report that cultured cerebellar granule induced die by low potassium treatment Aβ-treated cortical neurons, Mecp2-e2 expression upregulated whereas Mecp2-e1 isoform downregulated. Knockdown protects from death, knockdown e1 no effect. Forced MeCP2-e2, but MeCP2-e1, promotes apoptosis otherwise healthy find interacts forkhead FoxG1, also FoxG1 shown promote neuronal survival its downregulation leads death. elevated inhibits neurotoxicity. neurotoxicity inhibited IGF-1, prevents death-associated expression, Akt, activation necessary for FoxG1-mediated neuroprotection. Finally, enhanced if suppressed or -haplodeficient mice. Our results indicate death this activity normally FoxG1. Reduced FoxG1expression frees MecP2-e2