Single-cell identity generated by combinatorial homophilic interactions between α, β, and γ protocadherins

Chan Aye Thu, Weisheng V. Chen, Rotem Rubinstein, Maxime Chevee, Holly N. Wolcott, Klara O. Felsovalyi, Juan Carlos Tapia, Lawrence Shapiro, Barry Honig, Tom Maniatis

Research output: Contribution to journalArticlepeer-review

Abstract

Individual mammalian neurons stochastically express distinct repertoires of α, β, and γ protocadherin (Pcdh) proteins, which function in neural circuit assembly. We report that all three subfamilies of clustered Pcdhs can engage in specific homophilic interactions, that cell surface delivery of Pcdhα isoforms requires cis interactions with other Pcdhs, and that the extracellular cadherin domain EC6 plays a critical role in this process. Examination of homophilic interactions between specific combinations of multiple Pcdh isoforms revealed that Pcdh combinatorial recognition specificities depend on the identity of all of the expressed isoforms. A single mismatched Pcdh isoform can interfere with these combinatorial homophilic interactions. A theoretical analysis reveals that assembly of Pcdh isoforms into multimeric recognition units and the observed tolerance for mismatched isoforms can generate cell surface diversity sufficient for single-cell identity. However, the competing demands of nonself discrimination and self-recognition place limitations on the mechanisms by which homophilic recognition units can function.

Original languageEnglish
Pages (from-to)1045-1059
Number of pages15
JournalCell
Volume158
Issue number5
DOIs
StatePublished - 28 Aug 2014
Externally publishedYes

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