SUMMARY
Expression of the Down syndrome cell-adhesion molecule (Dscam) is increased in the brains of patients with several neurological disorders. Although Dscam is critically involved in many aspects of neuronal development, little is known about either the mechanism that regulates its expression or the functional consequences of dysregulated Dscam expression. Here, we show that Dscam expression levels serve as an instructive code for the size control of presynaptic arbor. Two convergent pathways, involving dual leucine zipper kinase (DLK) and fragile X mental retardation protein (FMRP), control Dscam expression through protein translation. Defects in this regulation of Dscam translation lead to exuberant presynaptic arbor growth in Drosophila somatosensory neurons. Our findings demonstrate a previously unknown aspect of Dscam function and provide insights into how dysregulated Dscam may contribute to the pathogenesis of neurological disorders.
Dendrites and axons are two major neuronal compartments with differences that are critical for neuronal functions. To learn about the differential regulation of dendritic and axonal development, we conducted a genetic screen in Drosophila and isolated the dendritic arbor reduction 1 (dar1) mutants, which display defects in dendritic but not axonal growth. The dar1 gene encodes a novel transcription regulator in the Krüppel-like factor family. Neurons lacking dar1 function have severely reduced growth of microtubule- but not F-actin-based dendritic branches. In contrast, overexpression of Dar1 dramatically increased the growth of microtubule-based dendritic branches. Our results suggest that Dar1 promotes dendrite growth in part by suppressing the expression of the microtubule severing protein Spastin. Our study thus uncovers a novel transcriptional program for microtubule regulation that preferentially controls dendrite growth.
Increased expression of Down Syndrome Cell Adhesion Molecule (Dscam) is implicated in the pathogenesis of brain disorders such as Down syndrome (DS) and fragile X syndrome (FXS). Here, we show that the cellular defects caused by dysregulated Dscam levels can be ameliorated by genetic and pharmacological inhibition of Abelson kinase (Abl) both in Dscam-overexpressing neurons and in a Drosophila model of fragile X syndrome. This study offers Abl as a potential therapeutic target for treating brain disorders associated with dysregulated Dscam expression.DOI:
http://dx.doi.org/10.7554/eLife.05196.001
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.