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Overexpression of Down syndrome cell adhesion molecule impairs precise synaptic targeting

Abstract

Fragile X syndrome is caused by the loss of Fragile X mental retardation protein (FMRP), an RNA-binding protein that suppresses protein translation. We found that FMRP binds to Down syndrome cell adhesion molecule (Dscam) RNA, a molecule that is involved in neural development and has been implicated in Down syndrome. Elevated Dscam protein levels in FMRP null Drosophila and in flies with three copies of the Dscam gene both produced specific and similar synaptic targeting errors in a hard-wired neural circuit, which impaired the flies' sensory perception. Reducing Dscam levels in FMRP null flies reduced synaptic targeting errors and rescued behavioral responses. Our results indicate that excess Dscam protein may be a common molecular mechanism underlying altered neural wiring in intellectual disabilities such as Fragile X and Down syndromes.

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Figure 1: FMRP suppresses Dscam protein translation.
Figure 2: The pSc mechanosensory neuron is identifiable between flies on the basis of the location of its corresponding bristle.
Figure 3: Elevated Dscam protein levels produce specific axonal targeting errors.
Figure 4: Errors in synaptic targeting impair touch perception.
Figure 5: FMRP binds multiple Dscam isoforms.

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Acknowledgements

The authors thank T.-J. Lin, I. Kays and V. Stoudenikina for assistance with experiments, R. Suciu for assistance in pyrosequencing analysis, A. Staffa and the Massively Parallel Sequencing Unit at Génome Québec for pyrosequencing assistance, and B. Douba for graphic arts assistance in the fly drawing. This work was supported by an Alfred P. Sloan Research Fellowship and a Canada Research Chair grant 950-212462 (to B.E.C.) and by funds from the Department of Medicine at McGill University and the Research Institute of the McGill University Health Centre.

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B.E.C. designed the experiments and supervised the project. V.C., A.D.H., F.E. and B.E.C. performed the experiments and analyzed the data. V.C., F.E. and B.E.C. wrote the manuscript.

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Correspondence to Brian E Chen.

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Cvetkovska, V., Hibbert, A., Emran, F. et al. Overexpression of Down syndrome cell adhesion molecule impairs precise synaptic targeting. Nat Neurosci 16, 677–682 (2013). https://doi.org/10.1038/nn.3396

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