Abstracts Category : Other

Local translation of Down syndrome cell adhesion moleculeand its implications for neural wiring defects

by Shruti Jain

Down syndrome cell adhesion molecule (Dscam) is knownto play an important role in many neurodevelopmental processes suchas axon guidance, dendrite arborization and synapse formation.DSCAM is located in the Down syndrome trisomic region of humanchromosome 21 and implicated as one of the genes directlycontributing to the Down syndrome brain phenotype, which includes areduction in the formation of neuronal connectivity. The localtranslation of a select group of mRNA transcripts within growthcones is an important mechanism regulating axon guidance and isnecessary for the formation of appropriate neuronal connectivity.Here, we find that netrin-1 stimulation induces DCC dependent localtranslation of Dscam mRNA in developing C57BL/6J mouse hippocampalgrowth cones. Furthermore, two RNA binding proteins, CPEB and FMRP,likely regulate Dscam mRNA localization and translation inhippocampal growth cones. Overexpression of DSCAM in mouse corticalpyramidal neurons results in a decrease in axon outgrowth andbranching. This finding directly implicates DSCAM as a contributorto the formation of improper neuronal connectivity in Downsyndrome. Interestingly, we have found that Dscam mRNA localizationand translation is dysregulated in early postnatal Ts65Dn mice, amouse model of Down syndrome. Ts65Dn growth cones also exhibit lossof responsiveness towards netrin-1, suggesting that the localtranslation of Dscam mRNA may be dysregulated in Down syndrome andcontribute to disrupted axon guidance in this disorder. Ts65Dnhippocampal neurons display reduced axon length in vitro, ascompared to their euploid littermates. In line with this, we findreduced interhemispheric connectivity in developing Ts65Dn mousebrains. Specifically, hippocampal commissure volume is reducedduring brain development in Down syndrome, which likely contributesto the impaired learning and memory phenotype of this disorder.This study is the first to report the presence of defectiveinterhemispheric connectivity at the time of birth in Ts65Dn mice,thus providing evidence that early therapeutic intervention may bethe most effective time window for the treatment of Down syndrome.Thus, this study elucidates an important molecular mechanismunderlying axon guidance that is dysregulated in Down syndromemice, and likely contributes to inappropriate neural connectivityand the etiology of this neurodevelopmental disorder.Advisors/Committee Members: Welshhans, Kristy (Advisor).