Signaling Mechanisms of Down Syndrome Cell Adhesion Molecule in Presynaptic Arbor Size Control.

Abstract

Increased expression of Down Syndrome Cell Adhesion Molecule (Dscam) is implicated in the pathogenesis of two common causes of intellectual disability, Down syndrome and Fragile X syndrome. Previous studies show that Dscam expression level is instructive for presynaptic arbor growth in Drosophila melanogaster, suggesting that targeting Dscam or its downstream signaling might prove therapeutic for disorders in which Dscam expression is increased. However, the signaling mechanisms that translate Dscam level into presynaptic arbor length are poorly known. We studied this issue in the Class IV dendritic arborization (C4da) neurons in Drosophila. Using epistasis analysis in C4da neurons, we found that Dscam requires Abelson tyrosine kinase (Abl) to promote presynaptic arbor growth. In addition, biochemical studies in both Drosophila Schneider 2 (S2) cell culture and neurons in vivo reveal that Dscam binds to and activates Abl. As proof of concept, we show that C4da presynaptic arbor defects caused by dysregulated Dscam levels can be ameliorated by pharmacological inhibition of Abl in a Drosophila model of Fragile X syndrome. In addition to identifying Abl as required for Dscam signaling, we used epistasis analysis in C4da neurons to identify Amyloid Precursor Protein-like (Appl), the Drosophila homolog of Amyloid Precursor Protein (APP), as a Dscam signaling partner. We show that Appl promotes presynaptic arbor growth and that Dscam and Appl are mutually required in C4da neurons. We also demonstrate that Appl, like Dscam, requires Abl. Finally, we show that simultaneous increases in Dscam and Appl expression lead to a synergistic defects in presynaptic arbor growth in C4da neurons. These results suggest that Dscam and Appl interact to control Abl activation and that concurrent increases in Dscam and Appl may act synergistically to contribute to the pathogenesis of disorders like Down syndrome and Fragile X syndrome. Importantly, these studies offer Abl as a potential therapeutic target for treating brain disorders associated with dysregulated Dscam expression.