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Protocadherins mediate dendritic self-avoidance in the mammalian nervous system

Nature volume 488, pages 517–521 (2012)Cite this article

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Abstract

Dendritic arborizations of many neurons are patterned by a process called self-avoidance, in which branches arising from a single neuron repel each other1,2,3,4,5,6,7. By minimizing gaps and overlaps within the arborization, self-avoidance facilitates complete coverage of a neuron’s territory by its neurites1,2,3. Remarkably, some neurons that display self-avoidance interact freely with other neurons of the same subtype, implying that they discriminate self from non-self. Here we demonstrate roles for the clustered protocadherins (Pcdhs) in dendritic self-avoidance and self/non-self discrimination. The Pcdh locus encodes 58 related cadherin-like transmembrane proteins, at least some of which exhibit isoform-specific homophilic adhesion in heterologous cells and are expressed stochastically and combinatorially in single neurons7,8,9,10,11. Deletion of all 22 Pcdh genes in the mouse γ-subcluster (Pcdhg genes) disrupts self-avoidance of dendrites in retinal starburst amacrine cells (SACs) and cerebellar Purkinje cells. Further genetic analysis of SACs showed that Pcdhg proteins act cell-autonomously during development, and that replacement of the 22 Pcdhg proteins with a single isoform restores self-avoidance. Moreover, expression of the same single isoform in all SACs decreases interactions among dendrites of neighbouring SACs (heteroneuronal interactions). These results suggest that homophilic Pcdhg interactions between sibling neurites (isoneuronal interactions) generate a repulsive signal that leads to self-avoidance. In this model, heteroneuronal interactions are normally permitted because dendrites seldom encounter a matched set of Pcdhg proteins unless they emanate from the same soma. In many respects, our results mirror those reported for Dscam1 (Down syndrome cell adhesion molecule) in Drosophila: this complex gene encodes thousands of recognition molecules that exhibit stochastic expression and isoform-specific interactions, and mediate both self-avoidance and self/non-self discrimination4,5,6,7,12,13,14,15. Thus, although insect Dscam and vertebrate Pcdh proteins share no sequence homology, they seem to underlie similar strategies for endowing neurons with distinct molecular identities and patterning their arborizations.

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Figure 1: Pcdhgs are required for self-avoidance of SAC dendrites.
Figure 2: Pcdhgs pattern developing SAC dendrites in a cell-autonomous manner.
Figure 3: No single Pcdhg isoform is necessary and any isoform is sufficient for dendrite self-avoidance.
Figure 4: Reducing Pcdhg diversity disrupts heteroneuronal SAC interactions.
Figure 5: Purkinje cell dendrite self-avoidance requires Pcdhg s.

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Acknowledgements

We thank members of our laboratory for providing advice and reagents, including D. Cai and K. Cohen (rAAV), I.-J. Kim (fstl4-line 1 mice) and M. Yamagata for modified Rosa-CAG targeting vector. We also thank B. Stevens (Children’s Hospital) for advice on culture methods. This work was supported by grants from NIH to J.R.S. (R01NS029169 and R01EY022073) and T.M. (R01NS043915) and NARSAD Young Investigator Award to J.L.L.

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Authors and Affiliations

  1. Center for Brain Science and Department of Molecular and Cellular Biology, Harvard University, 52 Oxford Street, Cambridge, Massachusetts 02138, USA,

    Julie L. Lefebvre, Dimitar Kostadinov & Joshua R. Sanes

  2. Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, 701 West 168th Street, New York, New York 10032, USA,

    Weisheng V. Chen & Tom Maniatis

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  1. Julie L. Lefebvre
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Contributions

J.L.L., D.K. and J.R.S. designed experiments and prepared the manuscript. J.L.L. and D.K. performed experiments and data analysis. J.R.S. supervised the project. W.V.C. and T.M. generated Pcdhgtako and Pcdhgtcko mice. All authors commented on the manuscript.

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Correspondence to Joshua R. Sanes.

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Lefebvre, J., Kostadinov, D., Chen, W. et al. Protocadherins mediate dendritic self-avoidance in the mammalian nervous system. Nature 488, 517–521 (2012). https://doi.org/10.1038/nature11305

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