Publication Date:
2012-07-31
Description:
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 gamma-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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3427422/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3427422/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lefebvre, Julie L -- Kostadinov, Dimitar -- Chen, Weisheng V -- Maniatis, Tom -- Sanes, Joshua R -- F31 NS078893/NS/NINDS NIH HHS/ -- R01 EY022073/EY/NEI NIH HHS/ -- R01 NS029169/NS/NINDS NIH HHS/ -- R01EY022073/EY/NEI NIH HHS/ -- R01NS029169/NS/NINDS NIH HHS/ -- R01NS043915/NS/NINDS NIH HHS/ -- T32 EY007110/EY/NEI NIH HHS/ -- England -- Nature. 2012 Aug 23;488(7412):517-21. doi: 10.1038/nature11305.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Brain Science and Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22842903" target="_blank"〉PubMed〈/a〉
Keywords:
Amacrine Cells/*cytology/*metabolism
;
Animals
;
Cadherins/genetics/*metabolism
;
Cell Adhesion Molecules/genetics/metabolism
;
Cells, Cultured
;
Dendrites/*metabolism
;
Drosophila Proteins/genetics/metabolism
;
Drosophila melanogaster/genetics/metabolism
;
Evolution, Molecular
;
Mice
;
Mice, Transgenic
;
Protein Isoforms/genetics/metabolism
;
Purkinje Cells/*cytology/*metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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