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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Available from: Weisheng Victor Chen, Oct 11, 2015
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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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    • "All mice were maintained on a C57BL/6 background. The lines used were reported previously: Pcdhg fcon3 (Lefebvre et al., 2008; Prasad et al., 2008; Lefebvre et al., 2012), Chat Cre (Rossi et al., 2011), Thy1-stop-YFP line #15 (Buffelli et al., 2003), Mnx1::eGFP (here called HB9-GFP) (Wichterle et al., 2002; Trenholm et al., 2011), RC-stop-tdTomato (Madisen et al., 2010), and RC-stop-PcdhgC3-mCherry (Lefebvre et al., 2012). "
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    ABSTRACT: Dendritic and axonal arbors of many neuronal types exhibit self-avoidance, in which branches repel each other. In some cases, these neurites interact with those of neighboring neurons, a phenomenon called self/non-self discrimination. The functional roles of these processes remain unknown. Here, we used retinal starburst amacrine cells (SACs), critical components of a direction-selective circuit, to address this issue. In SACs, both processes are mediated by the gamma-protocadherins (Pcdhgs), a family of 22 recognition molecules. We manipulated Pcdhg expression in SACs and recorded from them and their targets, direction-selective ganglion cells (DSGCs). SACs form autapses when self-avoidance is disrupted and fail to form connections with other SACs when self/non-self discrimination is perturbed. Pcdhgs are also required to prune connections between closely spaced SACs. These alterations degrade the direction selectivity of DSGCs. Thus, self-avoidance, self/non-self discrimination, and synapse elimination are essential for proper function of a circuit that computes directional motion.
    eLife Sciences 07/2015; 4. DOI:10.7554/eLife.08964 · 9.32 Impact Factor
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    • "Single g-Pcdh isoform expression rescues this selfavoidance defect, but leads to aberrant heteroneuronal avoidance of SAC dendrites. Lefebvre, et al., 2012 g-Pcdh knockdown of hippocampal neurons in vitro results in reduced dendritic arborization as well as activation of PYK2 and FAK and increased Rho inhibition. Constitutively active Rac1 rescues this phenotype. "
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    ABSTRACT: The proper formation of dendritic arbors is a critical step in neural circuit formation, and as such defects in arborization are associated with a variety of neurodevelopmental disorders. Among the best gene candidates are those encoding cell adhesion molecules, including members of the diverse cadherin superfamily characterized by distinctive, repeated adhesive domains in their extracellular regions. Protocadherins (Pcdhs) make up the largest group within this superfamily, encompassing over 80 genes, including the ∼60 genes of the α-, β-, and γ-Pcdh gene clusters and the non-clustered δ-Pcdh genes. An additional group includes the atypical cadherin genes encoding the giant Fat and Dachsous proteins and the 7-transmembrane cadherins. In this review we highlight the many roles that Pcdhs and atypical cadherins have been demonstrated to play in dendritogenesis, dendrite arborization, and dendritic spine regulation. Together, the published studies we discuss implicate these members of the cadherin superfamily as key regulators of dendrite development and function, and as potential therapeutic targets for future interventions in neurodevelopmental disorders.
    Cell adhesion & migration 04/2015; 9(3):1-13. DOI:10.1080/19336918.2014.1000069 · 4.51 Impact Factor
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