Human genetic studies support that loss of function mutations in the [highlight]SH[/highlight]3 domain and [highlight]ank[/highlight]yrin repeat containing family proteins (SHANK1-3), the large synaptic scaffolding proteins enriched at the postsynaptic density of excitatory synapses, are causative for autism spectrum disorder (ASD) and other neuropsychiatric disorders in humans. To better understand the in vivo functions of Shank and facilitate dissection of neuropathology associated with SHANK mutations in human, we generated multiple mutations in the Shank gene, the only member of the SHANK family in Drosophila melanogaster Both male and female Shank null mutants were fully viable and fertile with no apparent morphological or developmental defects. Expression analysis revealed apparent enrichment of Shank in the neuropils of the central nervous system. Specifically, Shank co-expressed with another PSD scaffold protein, Homer, in the calyx of mushroom bodies (MBs) in the brain. Consistent with high expression in MB calyces, Shank mutants show an abnormal calyx structure and reduced olfactory acuity. These morphological and functional phenotypes were fully rescued by pan-neuronal re-expression of Shank, and only partially rescued by pre- but no rescue by post-synaptic re-expression of Shank. Our findings thus establish a previously unappreciated pre-synaptic function of Shank. Key words: Shank; synaptic function; autism; PSD; mushroom body calyxSIGNIFICANCE STATEMENTMutations in SHANK family genes are causative for idiopathic ASD. To understand the neural function of Shank, a large scaffolding protein enriched at the postsynaptic densities, we examined the role of Drosophila Shank in synapse development at the peripheral neuromuscular junctions and the central MB calyx. Our results demonstrate that in addition to its conventional postsynaptic function, Shank also acts presynaptically in synapse development in the brain. This study offers novel insights into the synaptic role of Shank.
A pre-synaptic function of Shank protein in Drosophila