Skip to main content

Clustered Protocadherins

  • Chapter
  • First Online:
The Cadherin Superfamily

Abstract

Nearly 60 cadherin superfamily adhesion molecules are encoded by the Pcdha, Pcdhb, and Pcdhg gene clusters. These so-called clustered protocadherins (Pcdhs) are broadly expressed throughout the nervous system, with lower levels found in a few nonneuronal tissues. Each neuron expresses a limited repertoire of clustered Pcdh genes, in a complicated process controlled by differential methylation and promoter choice. The clustered Pcdh proteins interact homophilically in trans as cis-multimers, which has the potential to generate a combinatorially explosive number of distinct adhesive interfaces that may give neurons unique molecular identities important for circuit formation. Functional studies of animals in which clustered Pcdhs have been deleted or disrupted demonstrate that these proteins play critical roles in neuronal survival, axon and dendrite arborization, and synaptogenesis. Additionally, they have been implicated in the progression of several cancers, suggesting that basic studies of their function and signaling pathways will have important future clinical applications. This chapter reviews the extant literature on this fascinating and important group of cell adhesion molecules, the most diverse within the larger cadherin superfamily.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Banelli B, Brigati C, Di Vinci A, Casciano I, Forlani A, Borzì L, Allemanni G, Romani M (2011) A pyrosequencing assay for the quantitative methylation analysis of the PCDHB gene cluster, the major factor in neuroblastoma methylator phenotype. Lab Investig 92(3):458–465. doi:10.1038/labinvest.2011.169

    Article  PubMed  Google Scholar 

  • Blank M, Triana-Baltzer GB, Richards CS, Berg DK (2004) Alpha-protocadherins are presynaptic and axonal in nicotinic pathways. Mol Cell Neurosci 26(4):530–543

    Article  CAS  PubMed  Google Scholar 

  • Boggon TJ, Murray J, Chappuis-Flament S, Wong E, Gumbiner BM, Shapiro L (2002) C-cadherin ectodomain structure and implications for cell adhesion mechanisms. Science (New York, NY) 296 (5571):1308. doi:10.1126/science.1071559

    Google Scholar 

  • Bonn S, Seeburg P, Schwarz M (2007) Combinatorial Expression of {alpha}- and {gamma}-Protocadherins Alters Their Presenilin-Dependent Processing. Mol Cell Biol 27(11):4121. doi:10.1128/MCB.01708-06

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buchanan SM, Schalm SS, Maniatis T (2010) Proteolytic processing of protocadherin proteins requires endocytosis. Proc Natl Acad Sci USA 107(41):17774. doi:10.1073/pnas.1013105107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen J, Lu Y, Meng S, Han MH, Lin C, Wang X (2009) alpha- and gamma-Protocadherins negatively regulate PYK2. J Biol Chem 284(5):2880–2890. doi:10.1074/jbc.M807417200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen WV, Alvarez FJ, Lefebvre JL, Friedman B, Nwakeze C, Geiman E, Smith C, Thu CA, Tapia JC, Tasic B, Sanes JR, Maniatis T (2012) Functional significance of isoform diversification in the protocadherin gamma gene cluster. Neuron 75(3):402–409. doi:10.1016/j.neuron.2012.06.039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chong JA, Tapia-Ramirez J, Kim S, Toledo-Aral JJ, Zheng Y, Boutros MC, Altshuller YM, Frohman MA, Kraner SD, Mandel G (1995) REST: a mammalian silencer protein that restricts sodium channel gene expression to neurons. Cell 80(6):949–957

    Article  CAS  PubMed  Google Scholar 

  • Dallosso AR, Hancock AL, Szemes M, Moorwood K, Chilukamarri L, Tsai HH, Sarkar A, Barasch J, Vuononvirta R, Jones C, Pritchard-Jones K, Royer-Pokora B, Lee SB, Owen C, Malik S, Feng Y, Frank M, Ward A, Brown KW, Malik K (2009) Frequent long-range epigenetic silencing of protocadherin gene clusters on chromosome 5q31 in Wilms’ tumor. PLoS Genet 5(11):e1000745. doi:10.1371/journal.pgen.1000745

    Article  PubMed  PubMed Central  Google Scholar 

  • Dallosso AR, Oster B, Greenhough A, Thorsen K, Curry TJ, Owen C, Hancock AL, Szemes M, Paraskeva C, Frank M, Andersen CL, Malik K (2012) Long-range epigenetic silencing of chromosome 5q31 protocadherins is involved in early and late stages of colorectal tumorigenesis through modulation of oncogenic pathways. Oncogene 31(40):4409–4419. doi:10.1038/onc.2011.609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Emond MR, Jontes JD (2008) Inhibition of protocadherin-alpha function results in neuronal death in the developing zebrafish. Dev Biol 321(1):175

    Article  CAS  PubMed  Google Scholar 

  • Esumi S, Kakazu N, Taguchi Y, Hirayama T, Sasaki A, Hirabayashi T, Koide T, Kitsukawa T, Hamada S, Yagi T (2005) Monoallelic yet combinatorial expression of variable exons of the protocadherin-α gene cluster in single neurons. Nat Genet 37(2):171–176. doi:10.1038/ng1500

    Article  CAS  PubMed  Google Scholar 

  • Fernandez-Monreal M, Kang S, Phillips GR (2009) Gamma-protocadherin homophilic interaction and intracellular trafficking is controlled by the cytoplasmic domain in neurons. Mol Cell Neurosci 40(3):344–353. doi:10.1016/j.mcn.2008.12.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fernandez-Monreal M, Oung T, Hanson HH, O’Leary R, Janssen WG, Dolios G, Wang R, Phillips GR (2010) Gamma-protocadherins are enriched and transported in specialized vesicles associated with the secretory pathway in neurons. Eur J Neurosci 32(6):921. doi:10.1111/j.1460-9568.2010.07386.x

    Article  PubMed  PubMed Central  Google Scholar 

  • Frank M, Ebert M, Shan W, Phillips GR, Arndt K, Colman DR, Kemler R (2005) Differential expression of individual gamma-protocadherins during mouse brain development. Mol Cell Neurosci 29(4):603–616

    Article  CAS  PubMed  Google Scholar 

  • Fukuda E, Hamada S, Hasegawa S, Katori S, Sanbo M, Miyakawa T, Yamamoto T, Yamamoto H, Hirabayashi T, Yagi T (2008) Down-regulation of protocadherin-alpha A isoforms in mice changes contextual fear conditioning and spatial working memory. Eur J Neurosci 28(7):1362

    Article  PubMed  Google Scholar 

  • Garrett AM, Weiner JA (2009) Control of CNS synapse development by {gamma}-protocadherin-mediated astrocyte-neuron contact. J Neurosci 29(38):11723–11731. doi:10.1523/JNEUROSCI.2818-09.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garrett AM, Schreiner D, Lobas MA, Weiner JA (2012) gamma-protocadherins control cortical dendrite arborization by regulating the activity of a FAK/PKC/MARCKS signaling pathway. Neuron 74(2):269–276. doi:10.1016/j.neuron.2012.01.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • George SJ, Dwivedi A (2004) MMPs, cadherins, and cell proliferation. Trends Cardiovasc Med 14 (3):100–105. doi:http://dx.doi.org/10.1016/j.tcm.2003.12.008

    Google Scholar 

  • Gibson DA, Tymanskyj S, Yuan RC, Leung HC, Lefebvre JL, Sanes JR, Chedotal A, Ma L (2014) Dendrite self-avoidance requires cell-autonomous slit/robo signaling in cerebellar purkinje cells. Neuron 81(5):1040–1056. doi:10.1016/j.neuron.2014.01.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Golan-Mashiach M, Grunspan M, Emmanuel R, Gibbs-Bar L, Dikstein R, Shapiro E (2011) Identification of CTCF as a master regulator of the clustered protocadherin genes. Nucleic Acids Res. doi:10.1093/nar/gkr1260

    PubMed  PubMed Central  Google Scholar 

  • Gumbiner BM (2005) Regulation of cadherin-mediated adhesion in morphogenesis. Nat Rev Mol Cell Biol 6(8):622. doi:10.1038/nrm1699

    Article  CAS  PubMed  Google Scholar 

  • Guo Y, Monahan K, Wu H, Gertz J, Varley KE, Li W, Myers RM, Maniatis T, Wu Q (2012) CTCF/cohesin-mediated DNA looping is required for protocadherin alpha promoter choice. Proc Natl Acad Sci U S A 109(51):21081–21086. doi:10.1073/pnas.1219280110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haas IG, Frank M, Veron N, Kemler R (2005) Presenilin-dependent processing and nuclear function of gamma-protocadherins. J Biol Chem 280(10):9313–9319

    Article  CAS  PubMed  Google Scholar 

  • Hambsch B, Grinevich V, Seeburg PH, Schwarz MK (2005) gamma -protocadherins: Presenilin-mediated release of C-terminal fragment promotes locus expression. J Biol Chem 280:15888–15897

    Article  CAS  PubMed  Google Scholar 

  • Han MH, Lin C, Meng S, Wang X (2010) Proteomics analysis reveals overlapping functions of clustered protocadherins. Mol Cell Proteomics 9(1):71. doi:10.1074/mcp.M900343-MCP200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hanson HH, Kang S, Fernandez-Monreal M, Oung T, Yildirim M, Lee R, Suyama K, Hazan RB, Phillips GR (2010) LC3-dependent intracellular membrane tubules induced by gamma-protocadherins A3 and B2: a role for intraluminal interactions. J Biol Chem 285(27):20982–20992. doi:10.1074/jbc.M109.092031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hasegawa S, Hamada S, Kumode Y, Esumi S, Katori S, Fukuda E, Uchiyama Y, Hirabayashi T, Mombaerts P, Yagi T (2008) The protocadherin-alpha family is involved in axonal coalescence of olfactory sensory neurons into glomeruli of the olfactory bulb in mouse. Mol Cell Neurosci 38:66–79

    Article  CAS  PubMed  Google Scholar 

  • Hasegawa S, Hirabayashi T, Kondo T, Inoue K, Esumi S, Okayama A, Hamada S, Yagi T (2012) Constitutively expressed Protocadherin-alpha regulates the coalescence and elimination of homotypic olfactory axons through its cytoplasmic region. Front Mol Neurosci 5:97. doi:10.3389/fnmol.2012.00097

    Article  PubMed  PubMed Central  Google Scholar 

  • Hayashi S, Takeichi M (2015) Emerging roles of protocadherins: from self-avoidance to enhancement of motility. J Cell Sci 128:1455–1464. doi:10.1242/jcs.166306

    Article  CAS  PubMed  Google Scholar 

  • Hill E, Broadbent ID, Chothia C, Pettitt J (2001) Cadherin superfamily proteins in Caenorhabditis elegans and Drosophila melanogaster. J Mol Biol 305(5):1011. doi:10.1006/jmbi.2000.4361

    Article  CAS  PubMed  Google Scholar 

  • Hirano K, Kaneko R, Izawa T, Kawaguchi M, Kitsukawa T, Yagi T (2012) Single-neuron diversity generated by Protocadherin-β cluster in mouse central and peripheral nervous systems. Front Mol Neurosci 5:90. doi:10.3389/fnmol.2012.00090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hirayama T, Tarusawa E, Yoshimura Y, Galjart N, Yagi T (2012) CTCF is required for neural development and stochastic expression of clustered Pcdh genes in neurons. Cell Rep 2(2):345. doi:10.1016/j.celrep.2012.06.014

    Article  CAS  PubMed  Google Scholar 

  • Hulpiau P, van Roy F (2009) Molecular evolution of the cadherin superfamily. Int J Biochem Cell Biol 41(2):349–369. doi:10.1016/j.biocel.2008.09.027

    Article  CAS  PubMed  Google Scholar 

  • Hulpiau P, van Roy F (2011) New insights into the evolution of metazoan cadherins. Mol Biol Evol 28(1):647–657. doi:10.1093/molbev/msq233

    Article  CAS  PubMed  Google Scholar 

  • 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. Eur J Neurosci 27(3):559. doi:10.1111/j.1460-9568.2008.06052.x

    Article  PubMed  Google Scholar 

  • Kaneko R, Kato H, Kawamura Y, Esumi S, Hirayama T, Hirabayashi T, Yagi T (2006) Allelic gene regulation of Pcdh- and Pcdh- clusters involving both monoallelic and biallelic expression in single Purkinje cells. J Biol Chem 281(41):30551–30560. doi:10.1074/jbc.M605677200

    Article  CAS  PubMed  Google Scholar 

  • Kaneko R, Abe M, Hirabayashi T, Uchimura A, Sakimura K, Yanagawa Y, Yagi T (2014) Expansion of stochastic expression repertoire by tandem duplication in mouse Protocadherin-alpha cluster. Sci Rep 4:6263. doi:10.1038/srep06263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Katori S, Hamada S, Noguchi Y, Fukuda E, Yamamoto T, Yamamoto H, Hasegawa S, Yagi T (2009) Protocadherin-alpha family is required for serotonergic projections to appropriately innervate target brain areas. J Neurosci 29(29):9137–9147. doi:10.1523/JNEUROSCI.5478-08.2009

    Article  CAS  PubMed  Google Scholar 

  • Kawaguchi M, Toyama T, Kaneko R, Hirayama T, Kawamura Y, Yagi T (2008) Relationship between DNA methylation states and transcription of individual isoforms encoded by the protocadherin-alpha gene cluster. J Biol Chem 283:12064–12075

    Article  CAS  PubMed  Google Scholar 

  • Keeler AB, Molumby MJ, Weiner JA (2015) Protocadherins branch out: Multiple roles in dendrite development. Cell Adhes Migr 9(3):214–226. doi:10.1080/19336918.2014.1000069

    Article  CAS  Google Scholar 

  • Kehayova P, Monahan K, Chen W, Maniatis T (2011) Regulatory elements required for the activation and repression of the protocadherin-{alpha} gene cluster. Proc Natl Acad Sci 108:17195–17200. doi:10.1073/pnas.1114357108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kobayashi Y, Absher DM, Gulzar ZG, Young SR, McKenney JK, Peehl DM, Brooks JD, Myers RM, Sherlock G (2011) DNA methylation profiling reveals novel biomarkers and important roles for DNA methyltransferases in prostate cancer. Genome Res 21(7):1017–1027. doi:10.1101/gr.119487.110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):1137–1151

    Article  CAS  PubMed  Google Scholar 

  • Ledderose J, Dieter S, Schwarz MK (2013) Maturation of postnatally generated olfactory bulb granule cells depends on functional gamma-protocadherin expression. Sci Rep 3:1514. doi:10.1038/srep01514

    Article  PubMed  PubMed Central  Google Scholar 

  • Lefebvre J, Zhang Y, Meister M, Wang X, Sanes J (2008) {gamma}-Protocadherins regulate neuronal survival but are dispensable for circuit formation in retina. Development 135 (24):4141. doi:10.1242/dev.027912

    Google Scholar 

  • Lefebvre JL, Kostadinov D, Chen WV, Maniatis T, Sanes JR (2012) Protocadherins mediate dendritic self-avoidance in the mammalian nervous system. Nature 488(7412):517–521. doi:10.1038/nature11305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li Y, Serwanski DR, Miralles CP, Fiondella CG, Loturco JJ, Rubio ME, De Blas AL (2010) Synaptic and nonsynaptic localization of protocadherin-gammaC5 in the rat brain. J Comp Neurol 518(17):3439–3463. doi:10.1002/cne.22390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin C, Meng S, Zhu T, Wang X (2010) PDCD10/CCM3 acts downstream of {gamma}-protocadherins to regulate neuronal survival. J Biol Chem 285(53):41675–41685. doi:10.1074/jbc.M110.179895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McGowan PO, Suderman M, Sasaki A, Huang TCT, Hallett M, Meaney MJ, Szyf M (2011) PLOS ONE: broad epigenetic signature of maternal care in the brain of adult rats. PLoS One 6(2):e14739. doi:10.1371/journal.pone.0014739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meguro R, Hishida R, Tsukano H, Yoshitake K, Imamura R, Tohmi M, Kitsukawa T, Hirabayashi T, Yagi T, Takebayashi H, Shibuki K (2015) Impaired clustered protocadherin-alpha leads to aggregated retinogeniculate terminals and impaired visual acuity in mice. J Neurochem 33:66–72. doi:10.1111/jnc.13053

    Article  Google Scholar 

  • Morishita H, Yagi T (2007) Protocadherin family: diversity, structure, and function. Curr Opin Cell Biol 19(5):584

    Article  CAS  PubMed  Google Scholar 

  • Morishita H, Kawaguchi M, Murata Y, Seiwa C, Hamada S, Asou H, Yagi T (2004a) Myelination triggers local loss of axonal CNR/protocadherin alpha family protein expression. Eur J Neurosci 20(11):2843–2847

    Article  PubMed  Google Scholar 

  • Morishita H, Murata Y, Esumi S, Hamada S, Yagi T (2004b) CNR/Pcdhalpha family in subplate neurons, and developing cortical connectivity. Neuroreport 15(17):2595–2599

    Article  CAS  PubMed  Google Scholar 

  • Morishita H, Umitsu M, Murata Y, Shibata N, Udaka K, Higuchi Y, Akutsu H, Yamaguchi T, Yagi T, Ikegami T (2006) Structure of the cadherin-related neuronal receptor/protocadherin-alpha first extracellular cadherin domain reveals diversity across cadherin families. J Biol Chem 281(44):33650

    Article  CAS  PubMed  Google Scholar 

  • Murata Y, Hamada S, Morishita H, Mutoh T, Yagi T (2004) Interaction with protocadherin-gamma regulates the cell surface expression of protocadherin-alpha. J Biol Chem 279(47):49508

    Article  CAS  PubMed  Google Scholar 

  • Nelson WJ (2008) Regulation of cell–cell adhesion by the cadherin–catenin complex. Biochem Soc Trans 36(Pt 2):149–155. doi:10.1042/BST0360149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Niessen CM, Leckband D, Yap AS (2011) Tissue organization by cadherin adhesion molecules: dynamic molecular and cellular mechanisms of morphogenetic regulation. Physiol Rev 91(2):691–731. doi:10.1152/physrev.00004.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Noguchi Y, Hirabayashi T, Katori S, Kawamura Y, Sanbo M, Hirabayashi M, Kiyonari H, Nakao K, Uchimura A, Yagi T (2009) Total expression and dual gene-regulatory mechanisms maintained in deletions and duplications of the Pcdha cluster. J Biol Chem 284(46):32002–32014. doi:10.1074/jbc.M109.046938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nollet F, Kools P, van Roy F (2000) Phylogenetic analysis of the cadherin superfamily allows identification of six major subfamilies besides several solitary members. J Mol Biol 299(3):551–572

    Article  CAS  PubMed  Google Scholar 

  • Noonan J, Grimwood J, Danke J, Schmutz J, Dickson M, Amemiya C, Myers RM (2004a) Coelacanth genome sequence reveals the evolutionary history of vertebrate genes. Genome Res 14(1):2397–2405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Noonan JP, Grimwood J, Schmutz J, Dickson M, Myers RM (2004b) Gene conversion and the evolution of protocadherin gene cluster diversity. Genome Res 14(3):354–366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Novak P, Jensen TJ, Garbe JC, Stampfer MR, Futscher BW (2009) Stepwise DNA methylation changes are linked to escape from defined proliferation barriers and mammary epithelial cell immortalization. Cancer Res 69(12):5251–5258. doi:10.1158/0008-5472.can-08-4977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • O’Leary R, Reilly JE, Hanson HH, Kang S, Lou N, Phillips GR (2011) A variable cytoplasmic domain segment is necessary for gamma-protocadherin trafficking and tubulation in the endosome/lysosome pathway. Mol Biol Cell 22(22):4362–4372. doi:10.1091/mbc.E11-04-0283

    Article  PubMed  PubMed Central  Google Scholar 

  • Phillips GR, Huang JK, Wang Y, Tanaka H, Shapiro L, Zhang W, Shan WS, Arndt K, Frank M, Gordon RE, Gawinowicz MA, Zhao Y, Colman DR (2001) The presynaptic particle web: ultrastructure, composition, dissolution, and reconstitution. Neuron 32(1):63–77

    Article  CAS  PubMed  Google Scholar 

  • Phillips GR, Tanaka H, Frank M, Elste A, Fidler L, Benson DL, Colman DR (2003) Gamma-protocadherins are targeted to subsets of synapses and intracellular organelles in neurons. J Neurosci 23(12):5096–5104

    CAS  PubMed  Google Scholar 

  • Prasad T, Weiner JA (2011) Direct and indirect regulation of spinal cord Ia afferent terminal formation by the gamma-protocadherins. Front Mol Neurosci 4:54. doi:10.3389/fnmol.2011.00054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Prasad T, Wang X, Gray PA, Weiner JA (2008) A differential developmental pattern of spinal interneuron apoptosis during synaptogenesis: insights from genetic analyses of the protocadherin-gamma gene cluster. Development 135(24):4153–4164. doi:10.1242/dev.026807

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Puller C, Haverkamp S (2010) Cell-type-specific localization of protocadherin β16 at AMPA and AMPA/kainate receptor-containing synapses in the primate retina. J Comp Neurol 519(3):467–479. doi:10.1002/cne.22528

    Article  Google Scholar 

  • Ribich S, Tasic B, Maniatis T (2006) Identification of long-range regulatory elements in the protocadherin-alpha gene cluster. Proc Natl Acad Sci USA 103(52):19719. doi:10.1073/pnas.0609445104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rubinstein R, Thu CA, Goodman KM, Wolcott HN, Bahna F, Mannepalli S, Ahlsen G, Chevee M, Halim A, Clausen H, Maniatis T, Shapiro L, Honig B (2015) Molecular logic of neuronal self-recognition through protocadherin domain interactions. Cell 163(3):629–642. doi:10.1016/j.cell.2015.09.026

    Google Scholar 

  • Sano K, Tanihara H, Heimark RL, Obata S, Davidson M, St John T, Taketani S, Suzuki S (1993) Protocadherins: a large family of cadherin-related molecules in central nervous system. Embo J 12(6):2249–2256

    CAS  PubMed  PubMed Central  Google Scholar 

  • Schoenherr CJ, Anderson DJ (1995) The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes. Science 267(5202):1360–1363

    Article  CAS  PubMed  Google Scholar 

  • Schreiner D, Weiner JA (2010) Combinatorial homophilic interaction between gamma-protocadherin multimers greatly expands the molecular diversity of cell adhesion. Proc Natl Acad Sci U S A 107(33):14893–14898. doi:10.1073/pnas.1004526107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Severson PL, Tokar EJ, Vrba L, Waalkes MP, Futscher BW (2012) Agglomerates of aberrant DNA methylation are associated with toxicant-induced malignant transformation. Epigenetics 7(11):1238–1248. doi:10.4161/epi.22163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sotomayor M, Gaudet R, Corey DP (2014) Sorting out a promiscuous superfamily: towards cadherin connectomics. Trends Cell Biol 24 (9):524–536. doi:http://dx.doi.org/10.1016/j.tcb.2014.03.007

    Google Scholar 

  • Su H, Marcheva B, Meng S, Liang FA, Kohsaka A, Kobayashi Y, Xu AW, Bass J, Wang X (2010) Gamma-protocadherins regulate the functional integrity of hypothalamic feeding circuitry in mice. Dev Biol 339(1):38. doi:10.1016/j.ydbio.2009.12.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Suderman M, McGowan PO, Sasaki A, Huang TCT, Hallett MT, Meaney MJ, Turecki G, Szyf M (2012) Conserved epigenetic sensitivity to early life experience in the rat and human hippocampus. Proc Natl Acad Sci U S A 109:17266–17272

    Google Scholar 

  • Sugino H, Hamada S, Yasuda R, Tuji A, Matsuda Y, Fujita M, Yagi T (2000) Genomic organization of the family of CNR cadherin genes in mice and humans. Genomics 63(1):75–87. doi:10.1006/geno.1999.6066

    Article  CAS  PubMed  Google Scholar 

  • Sugino H, Yanase H, Hamada S, Kurokawa K, Asakawa S, Shimizu N, Yagi T (2004) Distinct genomic sequence of the CNR/Pcdhalpha genes in chicken. Biochem Biophys Res Commun 316(2):437–445. doi:10.1016/j.bbrc.2004.02.067

    Article  CAS  PubMed  Google Scholar 

  • Suo L, Lu H, Ying G, Capecchi MR, Wu Q (2012) Protocadherin clusters and cell adhesion kinase regulate dendrite complexity through Rho GTPase. J Mol Cell Biol 4(6):362–376. doi:10.1093/jmcb/mjs034

    Article  CAS  PubMed  Google Scholar 

  • Tada MN, Senzaki K, Tai Y, Morishita H, Tanaka YZ, Murata Y, Ishii Y, Asakawa S, Shimizu N, Sugino H, Yagi T (2004) Genomic organization and transcripts of the zebrafish Protocadherin genes. Gene 340(2):197–211. doi:10.1016/j.gene.2004.07.014

    Article  CAS  PubMed  Google Scholar 

  • Takeichi M (2007) The cadherin superfamily in neuronal connections and interactions. Nat Rev Neurosci 8(1):11. doi:10.1038/nrn2043

    Article  CAS  PubMed  Google Scholar 

  • Tan F, Ghosh S, Mbeunkui F, Thomas R, Weiner JA, Ofori-Acquah SF (2010) Essential role for ALCAM gene silencing in megakaryocytic differentiation of K562 cells. BMC Mol Biol 11:91. doi:10.1186/1471-2199-11-91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tasic B, Nabholz CE, Baldwin KK, Kim Y, Rueckert EH, Ribich SA, Cramer P, Wu Q, Axel R, Maniatis T (2002) Promoter choice determines splice site selection in protocadherin alpha and gamma pre-mRNA splicing. Mol Cell 10(1):21–33

    Article  CAS  PubMed  Google Scholar 

  • Thu CA, Chen WV, Rubinstein R, Chevee M, Wolcott HN, Felsovalyi KO, Tapia JC, Shapiro L, Honig B, Maniatis T (2014) Single-cell identity generated by combinatorial homophilic interactions between alpha, beta, and gamma protocadherins. Cell 158(5):1045–1059. doi:10.1016/j.cell.2014.07.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Toyoda S, Kawaguchi M, Kobayashi T, Tarusawa E, Toyama T, Okano M, Oda M, Nakauchi H, Yoshimura Y, Sanbo M, Hirabayashi M, Hirayama T, Hirabayashi T, Yagi T (2014) Developmental epigenetic modification regulates stochastic expression of clustered protocadherin genes, generating single neuron diversity. Neuron 82(1):94–108. doi:10.1016/j.neuron.2014.02.005

    Article  CAS  PubMed  Google Scholar 

  • Triana-Baltzer GB, Blank M (2006) Cytoplasmic domain of protocadherin-alpha enhances homophilic interactions and recognizes cytoskeletal elements. J Neurobiol 66(4):393. doi:10.1002/neu.20228

    Article  CAS  PubMed  Google Scholar 

  • Vanhalst K, Kools P, Vanden Eynde E, van Roy F (2001) The human and murine protocadherin-beta one-exon gene families show high evolutionary conservation, despite the difference in gene number. FEBS Lett 495(1-2):120–125

    Article  CAS  PubMed  Google Scholar 

  • Waha A, Guntner S, Huang TH, Yan PS, Arslan B, Pietsch T, Wiestler OD, Waha A (2005) Epigenetic silencing of the protocadherin family member PCDH-gamma-A11 in astrocytomas. Neoplasia 7(3):193–199. doi:10.1593/neo.04490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y, Liu H, Zhang Y, Ma D (1999) cDNA cloning and expression of an apoptosis-related gene, humanTFAR15 gene. Sci China Ser C-Life Sci 42(3):323–329. doi:10.1007/BF03183610

    Article  CAS  Google Scholar 

  • Wang X, Su H, Bradley A (2002a) Molecular mechanisms governing Pcdh-gamma gene expression: evidence for a multiple promoter and cis-alternative splicing model. Genes Dev 16(15):1890–1905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang X, Weiner JA, Levi S, Craig AM, Bradley A, Sanes JR (2002b) Gamma protocadherins are required for survival of spinal interneurons. Neuron 36(5):843–854

    Article  CAS  PubMed  Google Scholar 

  • Weiner JA, Wang X, Tapia JC, Sanes JR (2005) Gamma protocadherins are required for synaptic development in the spinal cord. Proc Natl Acad Sci U S A 102(1):8–14. doi:10.1073/pnas.0407931101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu Q (2001) Comparative DNA sequence analysis of mouse and human protocadherin gene clusters. Genome Res 11(3):389–404. doi:10.1101/gr.167301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu Q (2005) Comparative Genomics and Diversifying Selection of the Clustered Vertebrate Protocadherin Genes. Genetics 169:2179–2188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu Q, Maniatis T (1999) A striking organization of a large family of human neural cadherin-like cell adhesion genes. Cell 97:779–790

    Article  CAS  PubMed  Google Scholar 

  • Wu Q, Zhang T, Cheng JF, Kim Y, Grimwood J, Schmutz J, Dickson M, Noonan JP, Zhang MQ, Myers RM, Maniatis T (2001) Comparative DNA sequence analysis of mouse and human protocadherin gene clusters. Genome Res 11(3):389–404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yagi T (2012) Molecular codes for neuronal individuality and cell assembly in the brain. Front Mol Neurosci 5:45. doi:10.3389/fnmol.2012.00045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamashita H, Chen S, Komagata S, Hishida R, Iwasato T, Itohara S, Yagi T, Endo N, Shibata M, Shibuki K (2012) Restoration of Contralateral Representation in the Mouse Somatosensory Cortex after Crossing Nerve Transfer. PLoS One 7(4):e35676. doi:10.1371/journal.pone.0035676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yanase H, Sugino H, Yagi T (2004) Genomic sequence and organization of the family of CNR/Pcdhalpha genes in rat. Genomics 83(4):717–726. doi:10.1016/j.ygeno.2003.09.022

    Article  CAS  PubMed  Google Scholar 

  • Yokota S, Hirayama T, Hirano K, Kaneko R, Toyoda S, Kawamura Y, Hirabayashi M, Hirabayashi T, Yagi T (2011) Identification of the cluster control region for the protocadherin- genes located beyond the protocadherin- cluster. J Biol Chem 286(36):31885–31895. doi:10.1074/jbc.M111.245605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoshitake K, Tsukano H, Tohmi M, Komagata S, Hishida R, Yagi T, Shibuki K (2013) Visual map shifts based on whisker-guided cues in the young mouse visual cortex. Cell Rep 5(5):1365–1374. doi:10.1016/j.celrep.2013.11.006

    Article  CAS  PubMed  Google Scholar 

  • Yu WP, Yew K, Rajasegaran V, Venkatesh B (2007) Sequencing and comparative analysis of fugu protocadherin clusters reveal diversity of protocadherin genes among teleosts. BMC Evol Biol 7:49. doi:10.1186/1471-2148-7-49

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Kar Men Mah M.S. or Joshua A. Weiner Ph.D. .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Japan

About this chapter

Cite this chapter

Mah, K.M., Weiner, J.A. (2016). Clustered Protocadherins. In: Suzuki, S., Hirano, S. (eds) The Cadherin Superfamily. Springer, Tokyo. https://doi.org/10.1007/978-4-431-56033-3_8

Download citation

Publish with us

Policies and ethics