Mammalian Genome

, Volume 15, Issue 1, pp 41–52 | Cite as

Protocadherin X (PCDHX) and Y (PCDHY) genes; multiple mRNA isoforms encoding variant signal peptides and cytoplasmic domains

  • Patricia Blanco-Arias
  • Carole A. Sargent
  • Nabeel A. Affara
Article

Abstract

The gene-poor, hominid-specific Yp11.2/Xq21.3 X–Y homology block encodes two members of the protocadherin group of cell surface molecules, PCDHX and PCDHY. These two genes, mainly expressed in brain, were known to be composed of at least six exons sharing 98.1% DNA identity. The genomic structure of PCDHX/Y has been reanalyzed in detail, uncovering the existence of at least 11 more exons spanning more than 700 kb. Many of these exons located at the 5′ and 3′ ends of PCDHX/Y undergo differential and alternative splicing. Seven of the exons have been found to use alternative splice sites. Most of these variants are expressed within the brain, although some isoforms exhibit a more ubiquitous distribution pattern. PCDHX/Y transcription appears to be driven from two alternative promoters located usptream of exon 1 and exon 4.1. Assuming that the splicing events at the 5′ and 3′ ends of these genes are independent of one another, potentially up to 360 different mRNAs could be produced. The main impact on protein function is predicted to be in the efficiency of translation, post-translational processing within the cell, and structure of the cytoplasmic domain that may influence any role the genes have in signaling.

Notes

Acknowledgements

This work was supported by the Medical Research Council, Sygen, and the Isaac Newton Trust. Sylvia Nyame provided preliminary sequence and expression data from the ESTs in the PCDHX/Y region. We thank María Giouzeli for sharing information about SNP discovery before publication.

References

  1. 1.
    Altschul, SF, Gish, W, Miller, W, Myers, EW, Lipman, DJ 1990Basic local alignment search tool.J Mol Biol215403410CrossRefPubMedGoogle Scholar
  2. 2.
    Angst, BD, Marcozzi, C, Magee, AI 2001The cadherin superfamily.J Cell Sci114625626PubMedGoogle Scholar
  3. 3.
    Blanco, P, Sargent, CA, Boucher, CA, Mitchell, M, Affara, NA 2000Conservation of PCDHX in mammals; expression of human X/Y genes predominantly in brain.Mamm Genome11906914CrossRefPubMedGoogle Scholar
  4. 4.
    Bradley, RS, Espeseth, A, Kintner, C 1998NF-protocadherin, a novel member of the cadherin superfamily, is required for Xenopus ectodermal differentiation.Curr Biol8325334PubMedGoogle Scholar
  5. 5.
    Brett, D, Pospisil, H, Valcarcel, J, Reich, J, Bork, P 2002Alternative splicing and genome complexity.Nat Genet302930CrossRefPubMedGoogle Scholar
  6. 6.
    Brown, JD, Moon, RT 1998Wnt signaling; why is everything so negative?Curr Opin Cell Biol10182187CrossRefPubMedGoogle Scholar
  7. 7.
    Chen, MW, Vacherot, F, De La Taille, A, Gil-Diez-De-Medina, S, Shen, R,  et al. 2002The emergence of protocadherin-PC expression during the acquisition of apoptosis-resistance by prostate cancer cells.Oncogene2178617871CrossRefPubMedGoogle Scholar
  8. 8.
    Clark, F, Thanaraj, TA 2002Categorization and characterization of transcript-confirmed constitutively and alternatively spliced introns and exons from human.Hum Mol Genet11451464CrossRefPubMedGoogle Scholar
  9. 9.
    Croft, L, Schandorff, S, Clark, F, Burrage, K, Arctander, P,  et al. 2000ISIS, the intron information system, reveals the high frequency of alternative splicing in the human genome.Nat Genet24340341PubMedGoogle Scholar
  10. 10.
    Duret, L, Mouchiroud, D, Gautier, C 1995Statistical analysis of vertebrate sequences reveals that long genes are scarce in GC-rich isochores.J Mol Evol40308317Google Scholar
  11. 11.
    Gumbiner, BM 1998Propagation and localization of Wnt signaling.Curr Opin Genet Dev8430435CrossRefPubMedGoogle Scholar
  12. 12.
    Hanke, J, Brett, D, Zastrow, I, Aydin, A, Delbruck, S,  et al. 1999Alternative splicing of human genes: more the rule than the exception?Trends Genet15389390CrossRefPubMedGoogle Scholar
  13. 13.
    Hirano, S, Yan, Q, Suzuki, ST 1999Expression of a novel protocadherin, OL-protocadherin, in a subset of functional systems of the developing mouse brain.J Neurosci199951005PubMedGoogle Scholar
  14. 14.
    Kim, CH, Oda, T, Itoh, M, Jiang, D, Artinger, KB,  et al. 2000Represser activity of Headless/Tcf3 is essential for vertebrate head formation.Nature407913916CrossRefPubMedGoogle Scholar
  15. 15.
    Kohmura, N, Senzaki, K, Hamada, S, Kai, N, Yasuda, R,  et al. 1998Diversity revealed by a novel family of cadherins expressed in neurons at a synaptic complex.Neuron2011371151PubMedGoogle Scholar
  16. 16.
    Kozak, M 1986Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes.Cell44283292PubMedGoogle Scholar
  17. 17.
    Krawczak, M, J, Reiss, DN, Cooper 1992The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences.Hum Genet904154Google Scholar
  18. 18.
    Lambson, B, Affara, NA, Mitchell, M, Ferguson-Smith, MA 1992Evolution of DNA sequence homologies between the sex chromosomes in primate species.Genomics1410321040PubMedGoogle Scholar
  19. 19.
    Lander, ES, Linton, LM, Birren, B, Nusbaum, C, Zody, MC,  et al. 2001Initial sequencing and analysis of the human genome.Nature409860921PubMedGoogle Scholar
  20. 20.
    López, AJ 1998Alternative splicing of pre-mRNA: developmental consequences and mechanisms of regulation.Annu Rev Genet32279305CrossRefPubMedGoogle Scholar
  21. 21.
    McCrea, PD, Turck, CW, Gumbiner, B 1991A homolog of the armadillo protein in Drosophila (plakoglobin) associated with E-cadherin.Science25413591361PubMedGoogle Scholar
  22. 22.
    Mironov, AA, Fickett, JW, Gelfand, MS 1999Frequent alternative splicing of human genes.Genome Res912881293CrossRefPubMedGoogle Scholar
  23. 23.
    Modrek, B, Lee, C 2002A genomic view of alternative splicing.Nat Genet301319CrossRefPubMedGoogle Scholar
  24. 24.
    Modrek, B, Resch, A, Grasso, C, Lee, C 2001Genome-wide detection of alternative splicing in expressed sequences of human genes.Nucleic Acids Res2928502859CrossRefPubMedGoogle Scholar
  25. 25.
    Nissim-Rafinia, M, Kerem, B 2002Splicing regulation as a potential genetic modifier.Trends Genet18123127PubMedGoogle Scholar
  26. 26.
    Nollet, F, Kools, P, van Roy, F 2000Phylogenetic analysis of the cadherin superfamily allows identification of six major subfamilies besides several solitary members.J Mol Biol299551572PubMedGoogle Scholar
  27. 27.
    Obata, S, Sago, H, Mori, N, Rochelle, JM, Seldin, MF,  et al. 1995Protocadherin Pcdh2 shows properties similar to, but distinct from, those of classical cadherins.J Cell Sci10837653773PubMedGoogle Scholar
  28. 28.
    Ozawa, M, Kemler, R 1992Molecular organization of the uvomorulin-catenin complex.J Cell Biol116989996PubMedGoogle Scholar
  29. 29.
    Page, DC, Harper, ME, Love, J, Botstein, D 1984Occurrence of a transposition from the X-chromosome long arm to the Y-chromosome short arm during human evolution.Nature311119123PubMedGoogle Scholar
  30. 30.
    Redies, C 2000Cadherins in the central nervous system.Prog Neurobiol61611648PubMedGoogle Scholar
  31. 31.
    Rowen, L, Young, J, Birditt, B, Kaur, A, Madan, A,  et al. 2002Analysis of the human neurexin genes: alternative splicing and the generation of protein diversity.Genomics79587597CrossRefPubMedGoogle Scholar
  32. 32.
    Sago, H, Kitagawa, M, Obata, S, Mori, N, Taketani, S,  et al. 1995Cloning, expression, and chromosomal localization of a novel cadherin-related protein, protocadherin-3.Genomics29631640CrossRefPubMedGoogle Scholar
  33. 33.
    Sano, K, Tanihara, H, Heimark, RL, Obata, S, Davidson, M,  et al. 1993Protocadherins: a large family of cadherin-related molecules in central nervous system.EMBO J1222492256PubMedGoogle Scholar
  34. 34.
    Sargent, CA, Boucher, CA, Blanco, P, Chalmers, IJ, Highet, L,  et al. 2001Characterization of the human Xq21.3/Yp11 homology block and conservation of organization in primates.Genomics737785CrossRefPubMedGoogle Scholar
  35. 35.
    Sargent, CA, Briggs, H, Chalmers, IJ, Lambson, B, Walker, E,  et al. 1996The sequence organisation of YP/proximal xq homologous regions of the human sex chromosomes is highly conserved.Genomics32200209CrossRefPubMedGoogle Scholar
  36. 36.
    Schmucker, D, Clemens, JC, Shu, H, Worby, CA, Xiao, J,  et al. 2000Drosophila Dscam is an axon guidance receptor exhibiting extraordinary molecular diversity.Cell101671684PubMedGoogle Scholar
  37. 37.
    Senzaki, K, Ogawa, M, Yagi, T 1999Proteins of the CNR family are multiple receptors for Reelin.Cell99635647PubMedGoogle Scholar
  38. 38.
    Shapiro, L, Colman, DR 1999The diversity of cadherins and implications for a synaptic adhesive code in the CNS.Neuron23427430PubMedGoogle Scholar
  39. 39.
    Sharp, PA 1994Split genes and RNA splicing.Cell77805815PubMedGoogle Scholar
  40. 40.
    Smith, CW, Valcárcel, J 2000Alternative pre-mRNA splicing: the logic of combinatorial control.Trends Biochem Sci25381388CrossRefPubMedGoogle Scholar
  41. 41.
    Strehl, S, Glatt, K, Liu, QM, Glatt, H, Lalande, M 1998Characterization of two novel protocadherins (PCDH8 and PCDH9) localized on human chromosome 13 and mouse chromosome 14.Genomics538189CrossRefPubMedGoogle Scholar
  42. 42.
    Sugino, H, Hamada, S, Yasuda, R, Tuji, A, Matsuda, Y,  et al. 2000Genomic organization of the family of CNR cadherin genes in mice and humans.Genomics637587PubMedGoogle Scholar
  43. 43.
    Tabuchi, K, Sudhof, TC 2002Structure and evolution of neurexin genes: insight into the mechanism of alternative splicing.Genomics79849859CrossRefPubMedGoogle Scholar
  44. 44.
    Tatusova, TA, Madden, TL 1999BLAST 2 Sequences, a new tool for comparing protein and nucleotide sequences.FEMS Microbiol Lett174247250PubMedGoogle Scholar
  45. 45.
    Thanaraj, TA, Clark, F 2001Human GC-AG alternative intron isoforms with weak donor sites show enhanced consensus at acceptor exon positions.Nucleic Acids Res2925812593PubMedGoogle Scholar
  46. 46.
    Ullrich, B, Ushkaryov, YA, Sudhof, TC 1995Cartography of neurexins: more than 1000 isoforms generated by alternative splicing and expressed in distinct subsets of neurons.Neuron14497507PubMedGoogle Scholar
  47. 47.
    Ushkaryov, YA, Hata, Y, Ichtchenko, K, Moomaw, C, Afendis, S,  et al. 1994Conserved domain structure of beta-neurexins. Unusual cleaved signal sequences in receptor-like neuronal cell-surface proteins.J Biol Chem2691198711992PubMedGoogle Scholar
  48. 48.
    Venter, JC, Adams, MD, Myers, EW, Li, PW, Mural, RJ,  et al. 2001The sequence of the human genome.Science29113041351PubMedGoogle Scholar
  49. 49.
    Wu, Q, Maniatis, T 1999A striking organization of a large family of human neural cadherin-like cell adhesion genes.Cell97779790PubMedGoogle Scholar
  50. 50.
    Yagi, T, Takeichi, M 2000Cadherin superfamily genes: functions, genomic organization, and neurologic diversity.Genes Dev1411691180PubMedGoogle Scholar
  51. 51.
    Yamagata, K, Andreasson, KI, Sugiura, H, Maru, E, Dominique, M,  et al. 1999Arcadlin is a neural activity-regulated cadherin involved in long term potentiation.J Biol Chem2741947319479CrossRefPubMedGoogle Scholar
  52. 52.
    Yamamoto, A, Amacher, SL, Kim, SH, Geissert, D, Kimmel, CB,  et al. 1998Zebrafish paraxial protocadherin is a downstream target of spadetail involved in morphogenesis of gastrula mesoderm.Development12533893397PubMedGoogle Scholar
  53. 53.
    Yoshida, K, Sugano, S 1999Identification of a novel protocadherin gene (PCDH11) on the human XY homology region in Xq21.3.Genomics62540543CrossRefPubMedGoogle Scholar
  54. 54.
    Yoshida, K, Hida, M, Watanabe, M, Yamaguchi, R, Tateyama, S,  et al. 1999cDNA cloning and chromosomal mapping of mouse BH-protocadherin.DNA Seq104347PubMedGoogle Scholar

Copyright information

© Springer-Verlag New York Inc. 2004

Authors and Affiliations

  • Patricia Blanco-Arias
    • 1
  • Carole A. Sargent
    • 1
  • Nabeel A. Affara
    • 1
  1. 1.Human Molecular Genetics Group, Division of Cellular and Molecular Pathology, Department of PathologyUniversity of Cambridge, Tennis Court Road, Cambridge CB2 1QPUK

Personalised recommendations