Fragile X syndrome is caused by loss of Fragile X Mental Retardation Protein (FMRP), an RNA binding protein that suppresses protein translation. Here, we identified Down Syndrome Cell Adhesion Molecule (Dscam) RNA, a molecule involved in neural development and implicated in Down syndrome, bound to FMRP. Elevated Dscam protein levels in Drosophila FMRP null animals and in animals with three copies of the Dscam gene both produced specific and similar synaptic targeting errors in a hard-wired neural circuit which impaired the animal’s sensory perception. Reducing Dscam levels in FMRP null animals reduced synaptic targeting errors and rescued behavioral responses. Our results demonstrate that excess Dscam protein may be a common molecular mechanism underlying altered neural wiring in major causes of intellectual disability.

Establishing precise synaptic connectivity during development is crucial for neural circuit function. However, very few molecules have been identified that are involved in determining where and how many synapses form. The Plexin cell-surface molecules are a conserved family of axon guidance receptors that mediate axon fasciculation and repulsion during neural development, and later in development PlexinA receptors are involved in eliminating axonal branches and synapse numbers. Here we investigate the roles of PlexinA and PlexinB receptors in axonal branch and varicosity formation in Drosophila. We knocked down PlexinA or PlexinB expression using RNAi in identified mechanosensory neurons and analyzed axonal branching patterns and varicosity formations. Reducing PlexinA expression increased the axonal arbor complexity by increasing the number of branches and varicosities along the axon. In contrast, knocking down PlexinB expression decreased morphological complexity by decreasing the number of branches and the overall size of the axonal arbor, but did not reduce the number of varicosities. Our results demonstrate opposing roles for PlexinA and PlexinB in local wiring within a target region, where PlexinA functions to suppress excessive axonal branches and synapses and PlexinB facilitates axonal growth.