TY - JOUR
T1 - Single-cell identity generated by combinatorial homophilic interactions between α, β, and γ protocadherins
AU - Thu, Chan Aye
AU - Chen, Weisheng V.
AU - Rubinstein, Rotem
AU - Chevee, Maxime
AU - Wolcott, Holly N.
AU - Felsovalyi, Klara O.
AU - Tapia, Juan Carlos
AU - Shapiro, Lawrence
AU - Honig, Barry
AU - Maniatis, Tom
N1 - Funding Information:
We thank Dr. Richard Axel, Dr. Charles Zuker, Dr. Wesley Grueber, and Dr. Hemali Phatnani for critical reading of the manuscript and valuable comments. We also thank Lin Jin and Angelica Struve for technical assistance and members of the T.M., L.S., and B.H. labs for discussion and comments. We thank Dr. Joshua Sanes, Dr. Julie Lefebvre, Dr. Stefanie S. Schalm, and Dr. Steven Vogel for providing reagents and plasmids. This work was supported by a grant from NIH (2R56NS043915-33A1 to T.M.), a joint grant from NIH (1R01GM107571-01 to T.M. and L.S.), a grant from the National Science Foundation (MCB-0918535 to B.H.), and NIH Training Programs (T32GM008281 to H.N.W. and T32GM082797 to K.O.F.).
PY - 2014/8/28
Y1 - 2014/8/28
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84907301397&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2014.07.012
DO - 10.1016/j.cell.2014.07.012
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C2 - 25171406
AN - SCOPUS:84907301397
SN - 0092-8674
VL - 158
SP - 1045
EP - 1059
JO - Cell
JF - Cell
IS - 5
ER -