Cell
Volume 158, Issue 5, 28 August 2014, Pages 1045-1059
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Article
Single-Cell Identity Generated by Combinatorial Homophilic Interactions between α, β, and γ Protocadherins

https://doi.org/10.1016/j.cell.2014.07.012Get rights and content
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Highlights

  • Pcdhα, Pcdhβ, and Pcdhγ isoforms mediate specific homophilic interactions

  • EC6 domains of Pcdhα and PcdhγC4 isoforms inhibit cell surface delivery

  • Homophilic specificity of coexpressed Pcdh isoforms provides single-cell identity

  • Conflicting requirements of self-recognition and nonself discrimination

Summary

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.

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