Overexpression of Down syndrome cell adhesion molecule impairs precise synaptic targeting

In this study, the authors show that Dscam , a gene that has been implicated in Down syndrome, is targeted by the translation suppressor and Fragile X–linked protein FMRP. Loss of FMRP or overexpression of Dscam in Drosophila led to synaptic targeting errors and an impairment in perception of mechanical stimuli. Fragile X syndrome is caused by the loss of Fragile X mental retardation protein (FMRP), an RNA-binding protein that suppresses protein translation. We found that FMRP binds to Down syndrome cell adhesion molecule ( Dscam ) RNA, a molecule that is involved in neural development and has been implicated in Down syndrome. Elevated Dscam protein levels in FMRP null Drosophila and in flies with three copies of the Dscam gene both produced specific and similar synaptic targeting errors in a hard-wired neural circuit, which impaired the flies' sensory perception. Reducing Dscam levels in FMRP null flies reduced synaptic targeting errors and rescued behavioral responses. Our results indicate that excess Dscam protein may be a common molecular mechanism underlying altered neural wiring in intellectual disabilities such as Fragile X and Down syndromes.