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Dscam diversity is essential for neuronal wiring and self-recognition

Abstract

Neurons are thought to use diverse families of cell-surface molecules for cell recognition during circuit assembly. In Drosophila, alternative splicing of the Down syndrome cell adhesion molecule (Dscam) gene potentially generates 38,016 closely related transmembrane proteins of the immunoglobulin superfamily, each comprising one of 19,008 alternative ectodomains linked to one of two alternative transmembrane segments1. These ectodomains show isoform-specific homophilic binding, leading to speculation that Dscam proteins mediate cell recognition2. Genetic studies have established that Dscam is required for neural circuit assembly1,3,4,5,6,7,8,9,10, but the extent to which isoform diversity contributes to this process is not known. Here we provide conclusive evidence that Dscam diversity is essential for circuit assembly. Using homologous recombination, we reduced the entire repertoire of Dscam ectodomains to just a single isoform. Neural circuits in these mutants are severely disorganized. Furthermore, we show that it is crucial for neighbouring neurons to express distinct isoforms, but that the specific identity of the isoforms expressed in an individual neuron is unimportant. We conclude that Dscam diversity provides each neuron with a unique identity by which it can distinguish its own processes from those of other neurons, and that this self-recognition is essential for wiring the Drosophila brain.

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Figure 1: Generation and molecular characterization of Dscamsingle alleles.
Figure 2: Viability and neuronal wiring defects in Dscamsingle mutants.
Figure 3: Dscam diversity is required for mushroom body development.
Figure 4: Dscamsingle is sufficient to promote branch segregation with high fidelity at the single-cell level.

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Acknowledgements

We thank members of the Zipursky and Dickson laboratories for critical comments on the manuscript. This work was supported by grants from the Austrian Science Fund (B.J.D) and NIH (S.L.Z.). Work at the Institute of Molecular Pathology is also supported by funds from Boehringer Ingelheim GmbH. S.L.Z. is an Investigator of the Howard Hughes Medical Institute.

Author Contributions B.J.D. designed the targeting strategy, and E.D., E.V. and B.J.D. generated the Dscamsingle alleles, which were verified by E.D., D.H. and H.W.K. All biochemical and phenotypic analyses were performed by D.H., together with H.W.K. The intragenic MARCM strategy was conceived by D.H., E.D., H.W.K. and S.L.Z. B.J.D., D.H. and S.L.Z. wrote the manuscript.

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Correspondence to S. Lawrence Zipursky or Barry J. Dickson.

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Supplementary Figure

The file contains Supplementary Figure S1 which outlines the strategy used to isolate Dscamsingle and DscamFRT alleles. (PDF 174 kb)

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Hattori, D., Demir, E., Kim, H. et al. Dscam diversity is essential for neuronal wiring and self-recognition. Nature 449, 223–227 (2007). https://doi.org/10.1038/nature06099

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