Protocadherins (Pcdhs) are the largest mammalian subgroup of the cadherin superfamily of homophilic cell-adhesion proteins. They were discovered by Shintaro Suzuki's group, when they used PCR to find new members of the cadherin family. The PCR fragments that corresponded to Protocadherins were found in vertebrate and invertebrate species This prevalence in a wide range of species suggested that the fragments were part of an ancient cadherin and were thus termed "Protocadherins" as the "first cadherins"; although, of the approximately 70 Pcdh genes identified in mammalian genomes, over 50 are located in tightly linked gene clusters on the same chromosome, and this kind of organization can only be found in vertebrates.
In mammals, two types of Pcdh genes have been defined: the non-clustered Pcdhs which are scattered throughout the genome; and the clustered Pcdhs organized in three gene clusters designated α, β, γ which in mouse genome comprises 14, 22 and 22, respectively, large variable exons arrayed in tandem(Fig.1). Each exon is transcribed from its owner promoter and encodes: the entire extracellular domain, a transmembrane domain, and a short and variable intracellular domain of the corresponding Pcdh protein which differs from the Cadherin intracellular domain due to lack of attachment to the cytoskeleton through catenins(Fig.2).
Moreover, these clustered Pcdh genes are predominantly expressed in the developing nervous system  and since different subsets of Pcdhs genes are differentially expressed in individual neurons, a vast cell surface diversity may arise from this combinatorial expression. This has led to speculation and further to the proposal that Pcdhs may provide a synaptic-address code for neuronal connectivity or a single-cell barcode for self-recognition/self-avoidance similar to that ascribed to DSCAM proteins of invertebrates. Although vertebrate DSCAMs lack the diversity of their invertebrate counterparts, the selective transcription of individual Pcdh isoforms can be achieved by promoter choice followed by alternative pre-mRNA cis-splicing thus increasing the number of possible combinations.
Homophilic interactions and intracellular signaling
Clustered Pcdhs proteins are detected throughout the neuronal soma, dendrites and axons and are observed in synapses and growth cones. Like classical cadherins, members of Pcdhs family were also shown to mediate cell-cell adhesion in cell-based assays and most of them showed to engage in homophilic trans-interactions. Schreiner and Weiner  showed that Pcdhα and γ proteins can form multimeric complexes. If all three classes of Pcdhs could engage in multimerization of stochastically expressed Pcdhs isoforms, then neurons could produce a large number of distinct homophilic interaction units, amplifying significantly the cell-surface diversity more than the one afforded by stochastic gene expression alone. As for cytoplasmic domain, all the three classes of clustered Pcdhs proteins are dissimilar, although they are strictly conserved in vertebrate evolution, suggesting a conserved cellular function. This is corroborated by a large number of other interacting proteins including phosphatases, kinases, adhesion molecules and synaptic proteins The cytoplasmic domain also mediates intracellular retention, a property which distinguishes the clustered protocadherins from the related classical cadherins. Furthermore, it was shown that Pcdhs are proteolitically processed by γ-secretase complex, which releases soluble intracellular fragments into the cytoplasm which might have a broad range of functions as acting locally in the cytoplasm and/or even regulate gene expression similarly to other cell-surface proteins such as Notch and N-cadherin. Since these molecules are involved in so many developmental processes like axon guidance and dendrite ariborization, mutations in Pcdhs genes and their expression may play a role in Down, Rett as well as Fragile X syndrome, schizophrenia, and neurodegenerative diseases
- Neuronal self-avoidance
- Epileptic Encephalopathy, Early Infantile, 9, caused by mutation in the gene encoding protocadherin-19
- Hulpiau, P; Van Roy, F (2009). "Molecular evolution of the cadherin superfamily". The International Journal of Biochemistry & Cell Biology 41 (2): 349–69. doi:10.1016/j.biocel.2008.09.027. PMID 18848899.
- Sano, K; Tanihara, H; Heimark, R. L.; Obata, S; Davidson, M; St John, T; Taketani, S; Suzuki, S (1993). "Protocadherins: A large family of cadherin-related molecules in central nervous system". The EMBO journal 12 (6): 2249–56. PMC 413453. PMID 8508762.
- Chen, W. V.; Alvarez, F. J.; Lefebvre, J. L.; Friedman, B; Nwakeze, C; Geiman, E; Smith, C; Thu, C. A.; Tapia, J. C.; Tasic, B; Sanes, J. R.; Maniatis, T (2012). "Functional significance of isoform diversification in the protocadherin gamma gene cluster". Neuron 75 (3): 402–9. doi:10.1016/j.neuron.2012.06.039. PMC 3426296. PMID 22884324.
- Chen, W. V.; Maniatis, T (2013). "Clustered protocadherins". Development 140 (16): 3297–302. doi:10.1242/dev.090621. PMC 3737714. PMID 23900538.
- Kohmura, N; Senzaki, K; Hamada, S; Kai, N; Yasuda, R; Watanabe, M; Ishii, H; Yasuda, M; Mishina, M; Yagi, T (1998). "Diversity revealed by a novel family of cadherins expressed in neurons at a synaptic complex". Neuron 20 (6): 1137–51. PMID 9655502.
- Wang, X; Weiner, J. A.; Levi, S; Craig, A. M.; Bradley, A; Sanes, J. R. (2002). "Gamma protocadherins are required for survival of spinal interneurons". Neuron 36 (5): 843–54. PMID 12467588.
- Kallenbach, S; Khantane, S; Carroll, P; Gayet, O; Alonso, S; Henderson, C. E.; Dudley, K (2003). "Changes in subcellular distribution of protocadherin gamma proteins accompany maturation of spinal neurons". Journal of Neuroscience Research 72 (5): 549–56. doi:10.1002/jnr.10618. PMID 12749019.
- Phillips, G. R.; Tanaka, H; Frank, M; Elste, A; Fidler, L; Benson, D. L.; Colman, D. R. (2003). "Gamma-protocadherins are targeted to subsets of synapses and intracellular organelles in neurons". The Journal of neuroscience : the official journal of the Society for Neuroscience 23 (12): 5096–104. PMID 12832533.
- Junghans, D; Heidenreich, M; Hack, I; Taylor, V; Frotscher, M; Kemler, R (2008). "Postsynaptic and differential localization to neuronal subtypes of protocadherin beta16 in the mammalian central nervous system". European Journal of Neuroscience 27 (3): 559–71. doi:10.1111/j.1460-9568.2008.06052.x. PMID 18279309.
- Obata, S; Sago, H; Mori, N; Rochelle, J. M.; Seldin, M. F.; Davidson, M; St John, T; Taketani, S; Suzuki, S. T. (1995). "Protocadherin Pcdh2 shows properties similar to, but distinct from, those of classical cadherins". Journal of cell science. 108 ( Pt 12): 3765–73. PMID 8719883.
- Frank, M; Ebert, M; Shan, W; Phillips, G. R.; Arndt, K; Colman, D. R.; Kemler, R (2005). "Differential expression of individual gamma-protocadherins during mouse brain development". Molecular and Cellular Neuroscience 29 (4): 603–16. doi:10.1016/j.mcn.2005.05.001. PMID 15964765.
- Reiss, K; Maretzky, T; Haas, I. G.; Schulte, M; Ludwig, A; Frank, M; Saftig, P (2006). "Regulated ADAM10-dependent ectodomain shedding of gamma-protocadherin C3 modulates cell-cell adhesion". Journal of Biological Chemistry 281 (31): 21735–44. doi:10.1074/jbc.M602663200. PMID 16751190.
- Schreiner, D; Weiner, J. A. (2010). "Combinatorial homophilic interaction between gamma-protocadherin multimers greatly expands the molecular diversity of cell adhesion". Proceedings of the National Academy of Sciences 107 (33): 14893–8. doi:10.1073/pnas.1004526107. PMC 2930437. PMID 20679223.
- Schalm, S. S.; Ballif, B. A.; Buchanan, S. M.; Phillips, G. R.; Maniatis, T (2010). "Phosphorylation of protocadherin proteins by the receptor tyrosine kinase Ret". Proceedings of the National Academy of Sciences 107 (31): 13894–9. doi:10.1073/pnas.1007182107. PMC 2922223. PMID 20616001.
- Fernández-Monreal, M; Kang, S; Phillips, G. R. (2009). "Gamma-protocadherin homophilic interaction and intracellular trafficking is controlled by the cytoplasmic domain in neurons". Molecular and Cellular Neuroscience 40 (3): 344–53. doi:10.1016/j.mcn.2008.12.002. PMC 2646808. PMID 19136062.
- Bonn, S; Seeburg, P. H.; Schwarz, M. K. (2007). "Combinatorial expression of alpha- and gamma-protocadherins alters their presenilin-dependent processing". Molecular and Cellular Biology 27 (11): 4121–32. doi:10.1128/MCB.01708-06. PMC 1900011. PMID 17403907.
- Buchanan, S. M.; Schalm, S. S.; Maniatis, T (2010). "Proteolytic processing of protocadherin proteins requires endocytosis". Proceedings of the National Academy of Sciences 107 (41): 17774–9. doi:10.1073/pnas.1013105107. PMC 2955128. PMID 20876099.
- Kaufmann, W. E.; Moser, H. W. (2000). "Dendritic anomalies in disorders associated with mental retardation". Cerebral cortex (New York, N.Y. : 1991) 10 (10): 981–91. PMID 11007549.
- Kalmady, S. V.; Venkatasubramanian, G (2009). "Evidence for positive selection on Protocadherin Y gene in Homo sapiens: Implications for schizophrenia". Schizophrenia Research 108 (1–3): 299–300. doi:10.1016/j.schres.2008.09.015. PMID 18938061.
- Anderton, B. H.; Callahan, L; Coleman, P; Davies, P; Flood, D; Jicha, G. A.; Ohm, T; Weaver, C (1998). "Dendritic changes in Alzheimer's disease and factors that may underlie these changes". Progress in neurobiology 55 (6): 595–609. PMID 9670220.