Abstract
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.
Highlights
Down Syndrome Cell Adhesion Molecule (Dscam) levels are increased in the brains of human patients with Down syndrome (DS) and in mouse models of DS (Saito et al, 2000; Alves-Sampaio et al, 2010)
Recent research suggests that fragile X mental retardation protein (FMRP) binds directly to the mRNAs of Dscam from mouse brain (Brown et al, 2001; Darnell et al, 2011), and studies in Drosophila neurons further confirmed that FMRP suppresses Dscam translation (Cvetkovska et al, 2013; Kim et al, 2013)
We took advantage of the Drosophila larval class IV dendritic arborization (C4da) neurons to delineate the molecular mechanism of Dscam signaling in presynaptic arbor development, because the presynaptic terminal growth of these neurons is highly sensitive to Dscam levels in a linear fashion (Kim et al, 2013)
Summary
Dscam levels are increased in the brains of human patients with DS and in mouse models of DS (Saito et al, 2000; Alves-Sampaio et al, 2010). In the dendritic arborization (da) neurons in Drosophila larva, Dscam expression level is instructive for presynaptic terminal growth (Kim et al, 2013). We found that C4da presynaptic terminals overexpressing Abl-K417N were indistinguishable from wild-type (Figure 1D,E), indicating that Abl kinase activity is required.
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