Protocadherins mediate dendritic self-avoidance in the mammalian nervous system

Center for Brain Science and Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Nature (Impact Factor: 41.46). 07/2012; 488(7412):517-21. DOI: 10.1038/nature11305
Source: PubMed


Dendritic arborizations of many neurons are patterned by a process called self-avoidance, in which branches arising from a single neuron repel each other. By minimizing gaps and overlaps within the arborization, self-avoidance facilitates complete coverage of a neuron’s territory by its neurites. 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 neurons. 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 discrimination. 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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    • "Mice lacking all 22 genes of the protocadherin gamma cluster have decreased numbers of spinal cord synapses, are nearly immobile, and die shortly after birth [167]. More recent study showed that protocadherins were involved in mediating dendritic self-avoidance process, in which branches arising from a single neuron repel each other, in the mammalian retinal starburst amacrine interneurons and cerebellar Purkinje cells, mirroring those reported for Dscam1 function in Drosophila mentioned above [168]. The clustered protocadherins regulate neuronal survival, as well as dendritic self-avoidance. "
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    • "The a and g gene clusters also encode a small set of ''C-type'' Pcdhs, which are divergent from other members of their respective clusters and appear to have distinct functions (Figure 1A) (Chen et al., 2012). Deletion of the Pcdhg gene cluster in mice leads to the disruption of self-avoidance in retinal starburst amacrine cells and Purkinje cells with phenotypes similar to those described for Dscam1 deletion mutants in Drosophila (Lefebvre et al., 2012). Like invertebrate Dscam proteins, Pcdh isoforms engage in isoform-specific trans homophilic interactions (Schreiner and Weiner, 2010; Thu et al., 2014). "
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    ABSTRACT: Self-avoidance, a process preventing interactions of axons and dendrites from the same neuron during development, is mediated in vertebrates through the stochastic single-neuron expression of clustered protocadherin protein isoforms. Extracellular cadherin (EC) domains mediate isoform-specific homophilic binding between cells, conferring cell recognition through a poorly understood mechanism. Here, we report crystal structures for the EC1-EC3 domain regions from four protocadherin isoforms representing the α, β, and γ subfamilies. All are rod shaped and monomeric in solution. Biophysical measurements, cell aggregation assays, and computational docking reveal that trans binding between cells depends on the EC1-EC4 domains, which interact in an antiparallel orientation. We also show that the EC6 domains are required for the formation of cis-dimers. Overall, our results are consistent with a model in which protocadherin cis-dimers engage in a head-to-tail interaction between EC1-EC4 domains from apposed cell surfaces, possibly forming a zipper-like protein assembly, and thus providing a size-dependent self-recognition mechanism.
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    • "The diverse neuronal cell-surface PCDH repertoires, encoded by more than 50 clustered mammalian Pcdh genes, provide individual neurons with ''identity tags'' that engage in highly specific combinatorial homophilic interactions (Chen and Maniatis, 2013; Hirayama et al., 2012; Schreiner and Weiner, 2010; Thu et al., 2014; Wu, 2005; Wu and Maniatis, 1999). The functional significance of these interactions, based on direct evidence and by analogy to the Dscam system of invertebrates, is that they are required for the normal assembly of neural circuits during brain development (Chen et al., 2012; Garrett et al., 2012; Lefebvre et al., 2012; Suo et al., 2012; Thu et al., 2014; Wu and Maniatis, 1999). Therefore, understanding how PCDH diversity is generated in individual neurons is of fundamental importance. "
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    ABSTRACT: Graphical Abstract Highlights d The orientation of Pcdh CBSs determines the direction of topological DNA looping d Directional CTCF binding to CBSs is crucial for loop topology and gene expression d The CTCF binding orientation functions similarly in b-globin and the whole genome d CTCF/cohesin-mediated directional DNA-looping determines chromosome architecture
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