Protocadherins mediate dendritic self-avoidance in the mammalian nervous system

• Published in: Nature (London) Vol. 488; no. 7412; pp. 517 - 521
• Main Authors: Lefebvre, Julie L., Kostadinov, Dimitar, Chen, Weisheng V., Maniatis, Tom, Sanes, Joshua R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.08.2012; Nature Publishing Group
• Subjects: 631/378/1697; 631/378/2571; 631/80/79/1902; Adhesion; Amacrine Cells - cytology; Amacrine Cells - metabolism; Animals; Biological and medical sciences; Cadherins; Cadherins - genetics; Cadherins - metabolism; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Cells, Cultured; Cerebellum; Chromosome aberrations; Dendrites; Dendrites - metabolism; Dendritic cells; Drosophila; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Evolution, Molecular; Eye and associated structures. Visual pathways and centers. Vision; Fundamental and applied biological sciences. Psychology; Humanities and Social Sciences; Insects; letter; Medical genetics; Medical sciences; Mice; Mice, Transgenic; Multiculturalism & pluralism; multidisciplinary; Nervous system; Physiological aspects; Protein Isoforms - genetics; Protein Isoforms - metabolism; Proteins; Purkinje Cells - cytology; Purkinje Cells - metabolism; Retina; Science; Vertebrates: nervous system and sense organs; United States; Cerebellum; Transmembrane protein; Molecular form; Amacrine neuron; Rodentia; Central nervous system; Purkinje neuron; Retina; Nervous system; Down syndrome; Cadherin; Adhesion; Encephalon; Dendrite; Eye; Visual system; Vertebrata; Discrimination; Mammalia; Mouse; Animal; Avoidance
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature11305

Protocadherins are found to potentially provide the molecular diversity and complexity required to promote dendritic self-avoidance in mouse retina and cerebellum. Dendrite self-avoidance in mammalian neurons The complex geometry of neurons helps to determine the patterns of connectivity that underlie their functions. Elaborate axonal and dendritic patterning is achieved through self-avoidance, a process that allows individual branches of one neuron to repel each other while simultaneously attracting branches of other, seemingly identical neurons. The molecular basis of neurite self-avoidance in Drosophila involves Dscam genes, but the mammalian homologues are insufficiently complex to cope with self/non-self recognition. Here it is shown that protocadherins, a type of cell-adhesion molecule, may provide the molecular diversity and complexity required to promote dendritic self-avoidance in the mouse retina and cerebellum. Dendritic arborizations of many neurons are patterned by a process called self-avoidance, in which branches arising from a single neuron repel each other 1 , 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 neurites 1 , 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 neurons 7 , 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 discrimination 4 , 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.