FMR1 genetically interacts with DISC1 to regulate glutamatergic synaptogenesis.

Abstract

Synaptic development and functions have been hypothesized as crucial mechanisms of diverse neuropsychiatric disorders. Studies in past years suggest that mutations in the fragile X mental retardation 1 (FMR1) are associated with diverse mental disorders including intellectual disability, autistic spectrum disorder, and schizophrenia. In this study, we have examined genetical interactions between a select set of risk factor genes using fruit flies to find that dfmr1, the Drosophila homolog of the human FMR1 gene, exhibits functional interactions with DISC1 in synaptic development. We show that DISC1 overexpression in the dfmr1^null heterozygous background causes synaptic alterations at the larval neuromuscular junctions that are distinct from those in the wild-type background. Loss of dfmr1 modifies the DISC1 overexpression phenotype in synaptic formation, suppressing the formation of synapse boutons. Interaction between the two genes was further supported molecularly by the results that dfmr1 mutations suppress the DISC1-mediated upregulations of the postsynaptic expression of a glutamate receptor and the expression of ELKS/CAST protein, Bruchpilot, in presynaptic motoneurons. Moreover, DISC1 overexpression in the dfmr1^null heterozygous background causes downregulation of a MAP1 family protein, Futsch. These results thus suggest an intriguing converging mechanism controlled by FMR1 and DISC1 in the developing glutamatergic synapses.