RBPs in ASD

Molecular Targets for ASD

Defects in RNA regulation in the nervous system lead to neurodevelopmental dysfunction (e.g. autism) and neurodegenerative diseases (e.g. ALS). The mechanisms by which RBPs cause neurological disease are diverse, and in several cases the molecular details continue to remain elusive.

RBFOX1, RBFOX2, RBFOX3. Rbfox proteins interact with proteins mutated in spinal cerebellar ataxia and individuals with mutations mapping to the Rbfox1 gene locus have mental retardation, epilepsy and autism. Animal models with knockout or knockdown of Rbfox protein expression show extensive defects in neuronal physiology. To test the hypothesis that alternative splicing targets of Rbfox proteins would reveal pathways important in autism, we mapped the Rbfox 1 and 2 transcriptome-wide binding sites in mouse brains. We were excited to find that loci associated with autism spectrum disorders such as the Neurexins, Neuroligins and Shank genes contained both Rbfox sites nearby alternatively spliced exons but interestingly, also far away from any exons (LovcWe et al.). With further exploration, we found that similarly to exon-proximal sites, distal sites bound by Rbfox1 and Rbfox2 contain evolutionarily conserved GCAUG sequences and are associated with splicing regulation upon modulation of Rbfox abundance. We showed that a conserved long-range RNA-RNA base-pairing interaction (an “RNA bridge”) facilitates Rbfox-mediated exon inclusion in the ENAH (enabled homology) gene, demonstrating, a fundamental RNA-mediated mechanism for AS control by distally bound RBPs (Lovci et al.).