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Architecture of the X Chromosome, Expression of LIM Kinase 1, and Recombination in the agnostic Mutants of Drosophila: A Model for Human Williams Syndrome

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Abstract

As the Human Genome and Drosophila Genome Projects were completed, it became clear that functions of human disease-associated genes may be elucidated by studying the phenotypic expression of mutations affecting their structural or functional homologs in Drosophila.Genomic diseases were identified as a new class of human disorders. Their cause is recombination, which takes place at gene-flanking duplicons to generate chromosome aberrations such as deletions, duplications, inversions, and translocations. The resulting imbalance of the dosage of developmentally important genes arises at a frequency of 10-3 (higher than the mutation rate of individual genes) and leads to syndromes with multiple manifestations, including cognitive defects. Genomic DNA fragments were cloned from the Drosophila melanogaster agnostic locus, whose mutations impair learning ability and memory. As a result, the locus was exactly localized in X-chromosome region 11AB containing the LIM kinase 1 (LIMK1) gene (CG1848), which is conserved among many species. Hemizygosity for the LIMK1 gene, which is caused by recombination at neighboring extended repeats, underlies cognitive disorders in human Williams syndrome. LIMK1 is a component of the integrin signaling cascade, which regulates the functions of the actin cytoskeleton, synaptogenesis, and morphogenesis in the developing brain. Immunofluorescence analysis revealed LIMK1 in all subdomains of the central complex and the visual system of Drosophila melanogaster.Like in the human genome, theD. melanogaster region is flanked by numerous repeats, which were detected by molecular genetic methods and analysis of ectopic chromosome pairing. The repeats determined a higher rate of spontaneous and induced recombination, including unequal crossing over, in theagnostic gene region. Hence, the agnostic locus was considered as the first D. melanogaster model suitable for studying the genetic defect associated with Williams syndrome in human.

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REFERENCES

  1. Adams, M.D., Celniker, S.E., Holt, R.A., et al., The Genome Sequence of Drosophila melanogaster, Science, 2000, vol. 287, pp. 2185-2195, http://flybase.bio.indiana.edu.

    Google Scholar 

  2. Venter, J.C., Adams, M.D., Myers, E.W., et al., The Sequence of the Human Genome, Science, 2001, vol. 291, pp. 1304-1351.

    Google Scholar 

  3. Rubin, G.M., Yandell, M.D., Wortman, J.R., et al., Comparative Genomics of the Eukaryotes, Science, 2000, vol. 287, pp. 2204-2215.

    Google Scholar 

  4. Huala, E., Dickerman, A.W., Garcia-Hernandez, M., et al., The Arabidopsis Information Resource (TAIR): A Comprehensive Database and Web-Based Information Retrieval, Analysis, and Visualization System for a Model Plant, Nucleic Acids Res., 2001, vol. 29, pp. 102-105.

    Google Scholar 

  5. Ji, Y., Eichler, E.E., Schwartz, S., and Nicholls, R.D., Structure of Chromosomal Duplicons and Their Role in Mediating Human Genomic Disorders, Genome Res., 2000, vol. 10, pp. 597-610.

    Google Scholar 

  6. Purandare, S.M. and Patel, P.I., Recombination Hotspots and Human Disease, Genome Res., 1997, vol. 7, pp. 773-786.

    Google Scholar 

  7. Shaikh, T.H., Kurahashi, H., and Emanuel, B.S., Evolutionarily Conserved Low Copy Repeats (LCRs) in 22q11 Mediate Deletions, Duplications, Translocations, and Genomic Instability: An Update and Literature Review, Genet. Med., 2001, vol. 3, pp. 6-13.

    Google Scholar 

  8. Korenberg, J.R., Chen, X., Hirota, N., et al., Genome Structure and Cognitive Map of Williams Syndrome, J. Cogn. Neurosci., 2000, vol. 12, pp. S89-S107.

    Google Scholar 

  9. Peoples, R., Franke, Y., Wang, Y.K., et al., A Physical Map, Including a BAC/PAC Clone Contig, of the Williams-Beuren Syndrome Deletion Region at 7q11.23, Am. J. Hum. Genet., 2000, vol. 66, pp. 47-68.

    Google Scholar 

  10. Hawley, R.S., Chromosomal Sites Necessary for Normal Levels of Meiotic Recombination in Drosophila melanogaster: I. Evidence for and Mapping of the Sites, Genetics, 1980, vol. 94, pp. 625-646.

    Google Scholar 

  11. Kosikov, K.V., A New Duplication in the Drosophila melanogaster X Chromosome and Its Evolutionary Significance, Dokl. Akad. Nauk SSSR, 1936, vol. 3, pp. 297-300.

    Google Scholar 

  12. Zhimulev, I.F., Semeshin, V.F., Kulichkov, V.A., and Belyaeva, E.S., Intercalary Heterochromatin in Drosophila: Localisation and General Characteristics, Chromosoma, 1982, vol. 87, pp. 197-228.

    Google Scholar 

  13. Zhimulev, I.F., Polytene Chromosomes, Heterochromatin, and Position Effect Variegation, Adv. Genet., 1998, vol. 37, pp. 1-566.

    Google Scholar 

  14. Leach, T.J., Chotkowski, H.L., Wotring, M.G., et al., Replication of Heterochromatin and Structure of Polytene Chromosomes, Mol. Cell. Biol., 2000, vol. 20, pp. 6308-6316.

    Google Scholar 

  15. Xamena, N., Creus, A., and Macros, R., Effect of Intercalating Mutagens on Crossing Over in Drosophila melanogaster Females, Experientia, 1985, vol. 41, pp. 1078-1081.

    Google Scholar 

  16. Belyaeva, E.S., Zhimulev, I.F., Volkova, E.I., et al., Su(UR)ES: A Gene Suppressing DNA Underreplication in Intercalary and Pericentric Heterochromatin of Drosophila melanogaster Polytene Chromosomes, Proc. Natl. Acad. Sci. USA, 1998, vol. 95, pp. 7532-7537.

    Google Scholar 

  17. Savvateeva-Popova, E.V., Peresleni, A.I., Sharagina, L.M., et al., A Full-Range Study of the agnostic Mutants of Drosophila melanogaster: A Model to Associate Alterations of Genome Architecture and Cognitive Functions, Zh. Evolyuts. Biokhim. Fiziol., 2002, vol. 38,no. 6, pp. 557-577.

    Google Scholar 

  18. Reiter, L.T., Potocki, L., Chien, S., et al., A Systematic Analysis of Human Disease-Associated Gene Sequences in Drosophila melanogaster, Genome Res., 2001, vol. 11, pp. 1114-1125.

    Google Scholar 

  19. Savvateeva, E.V., Kamyshev, N.G., and Rozenblyum, S.R., Construction of Temperature-Sensitive Mutations Altering Metabolism of Cyclic 3′,5′-Adenosine Monophosphate in Drosophila melanogaster, Dokl. Akad. Nauk SSSR, 1978, vol. 240, pp. 1443-1445.

    Google Scholar 

  20. Savvateeva, E.V. and Kamyshev, N.G., Behavioral Effects of Temperature-Sensitive Mutations Affecting Metabolism of cAMP in D. melanogaster, Pharm. Biochem. Behav., 1981, vol. 14, pp. 603-611.

    Google Scholar 

  21. Savvateeva, E.V. and Kamyshev, N.G., The Effect of Mutations Affecting Metabolism of Cyclic 3′,5′-Adenosine Monophosphate on the Locomotor Activity and Learning in Drosophila melanogaster, Dokl. Akad. Nauk SSSR, 1978, vol. 243, pp. 1564-1567.

    Google Scholar 

  22. Savvateeva, E.V. and Korochkin, L.I., Adenylate Cyclase in Ts-Mutants of Drosophila melanogaster, Isozyme Bull., 1982, vol. 15, p. 21.

    Google Scholar 

  23. Savvateeva, E.V., Labazova, I.V., and Korochkin, L.I., A Study of Cyclic AMP Phosphodiesterase in Temperature-Sensitive Mutants of Drosophila melanogaster, Dokl. Akad. Nauk SSSR, 1981, vol. 258, pp. 748-753.

    Google Scholar 

  24. Savvateeva, E.V. and Korochkin, L.I., A Study of the Regulation of the cAMP Level in Drosophila melanogaster, Dokl. Akad. Nauk SSSR, 1981, vol. 260, pp. 481-484.

    Google Scholar 

  25. Savvateeva, E.V., Peresleni, I.V., and Korochkin, L.I., Ontogenetic Variation of Adenylate Cyclase and Phosphodiesterase in Temperature-Sensitive Drosophila melanogaster Mutants with Altered cAMP Metabolism, Dokl. Akad. Nauk SSSR, 1985, vol. 281, pp. 439-443.

    Google Scholar 

  26. Savvateeva, E.V., Peresleni, I.V., and Korochkin, L.I., Cyclic AMP and Locomotor Activity of Drosophila melanogaster, Dokl. Akad. Nauk SSSR, 1985, vol. 281, pp. 966-970.

    Google Scholar 

  27. Savvateeva, E.V., Peresleni, I.V., and Korochkin, L.I., Temperature-Sensitive Drosophila melanogaster Mutants with Altered cAMP Phosphodiesterase Activity: Has the Calmodulin Gene Been Found?, Dokl. Akad. Nauk SSSR, 1985, vol. 281, pp. 1233-1237.

    Google Scholar 

  28. Lopatina, N.G., Marshin, V.G., Ponomarenko, V.V., et al., A Study of the Neurophysiological Trait, Ether Anesthesia Rate, in Conjunction with Behavior in Insects (Drosophila, Honey Bee): I. The Character of Genetic and Ontogenetic Variations of Ether Anesthesia Rate in Drosophila and Honey Bee Strains and Selection of Drosophila Strains with Respect to This Trait, Genetika (Moscow), 1977, vol. 13, pp. 1767-1777.

    Google Scholar 

  29. Sharagina, L.M., Savvateeva, E.V., and Atamanenko, A.A., A Study of the Cyclic Nucleotide Phosphodiesterase Activity in Mutant Drosophila melanogaster Strains, Genetika (Moscow), 1997, vol. 33,no. 6, pp. 784-787.

    Google Scholar 

  30. Savvateeva, E.V., Peresleni, I.V., Ivanushina, V., and Korochkin, L.I., Expression of Adenylate Cyclase and Phosphodiesterase in Development of Temperature-Sensitive Mutants with Impaired Metabolism of cAMP in Drosophila melanogaster, Dev. Genet., 1985, vol. 5, pp. 159-172.

    Google Scholar 

  31. Savvateeva, E.V., Genetic Control of Secondary Messenger Systems and Their Role in Learning, Usp. Sovrem. Genet., 1991, no. 17, pp. 33-99.

    Google Scholar 

  32. Korochkina, S.E., Savvateeva, E.V., Klimenko, V.V., and Ponomarenko, V.V., Spontaneous and Temperature-Induced Recombination in Drosophila melanogaster Strains with Altered cAMP Metabolism, Dokl. Akad. Nauk SSSR, 1985, vol. 285, pp. 1454-1458.

    Google Scholar 

  33. Korochkina, S.E. and Savvateeva, E.V., A Study of Interstrain Gonad Grafting in D. melanogaster Females, Ontogenez (Moscow), 1985, pp. 521-523.

  34. Savvateeva, E.V., Korochkina, S.E., Peresleni, I.V., and Kamyshev, N.G., Map Expansion around Ts-Mutations in Genes Controlling cAMP Metabolism in Drosophila melanogaster, Dros. Inf. Serv., 1985, vol. 61, pp. 144-146.

    Google Scholar 

  35. Peresleni, A.I., Savvateeva, E.V., Peresleni, I.V., and Sharagina, L.M., Mutational Analysis and Genetic Cloning of the agnostic Locus Which Regulates Learning Ability in Drosophila, Neurosci. Behav. Physiol., 1997, vol. 27, pp. 258-263.

    Google Scholar 

  36. Medvedeva, A.V. and Savvateeva, E.V., The Effect of ts Mutations of the agnostic Gene, Which Controls the Calmodulin Function and Learning Ability, on Ectopic Pairing of Polytene Chromosomes in Drosophila melanogaster, Dokl. Akad. Nauk SSSR, 1991, vol. 318, pp. 733-736.

    Google Scholar 

  37. Medvedeva, A.V. and Savvateeva, E.V., The Effect of Temperature on the Spatial Organization of Polytene Chromosomes in Drosophila melanogaster Mutants with Altered Calmodulin Functions, Dokl. Akad. Nauk SSSR, 1991, vol. 318, pp. 988-991.

    Google Scholar 

  38. Sambrook, J., Fritsch, E.F., and Maniatis, T., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor, New York: Cold Spring Harbor Lab., 1989, vols. 1-3.

    Google Scholar 

  39. Kafatos, F.C., Loitus, C., Savakis, C., et al., Integrated Maps of the Drosophila Genome: Progress and Prospects, Trends Genet., 1991, vol. 7, pp. 155-161.

    Google Scholar 

  40. Lozovskaya, E.R., Petrov, D.A., and Hartl, D.L., A Combined Molecular and Cytogenetic Approach to Genome Evolution in Drosophila Using Large-Fragment DNA Cloning, Chromosoma, 1993, vol. 102, pp. 253-256.

    Google Scholar 

  41. Langer-Safer, P.R., Levine, M., and Ward, D.C., Immunological Method for Mapping Genes on Drosophila Polytene Chromosomes, Proc. Natl. Acad. Sci. USA, 1982, vol. 790, pp. 4381-4385.

    Google Scholar 

  42. Heisenberg, M. and Bohl, K., Isolation of Anatomical Brain Mutants of Drosophila by Histological Means, Z. Naturforsch., 1979, vol. 34, pp. 143-147.

    Google Scholar 

  43. Grell, R.F., Recombination and DNA Replication in D. melanogaster Oocyte, Genetics, 1973, vol. 73, pp. 87-108.

    Google Scholar 

  44. Bregliano, J.C., Picard, G., Bucheton, A., et al., Hybrid Dysgenesis in Drosophila melanogaster, Science, 1980, vol. 207, pp. 606-611.

    Google Scholar 

  45. Urbakh, V.Yu., Matematicheskaya statistika dlya biologov i medikov (Mathematical Statistics for Biologists and Medical Professionals), Moscow: Akad. Nauk SSSR, 1963.

    Google Scholar 

  46. Stevens, A., The Analysis of Interference, J. Genet., 1936, vol. 32, pp. 56-64.

    Google Scholar 

  47. Lenhoff, H.M., Wang, P.P., Greenberg, F., and Bellugi, U., Williams Syndrome and the Brain, Sci. Am., 1997, vol. 277, pp. 68-73.

    Google Scholar 

  48. Donnai, D. and Karmiloff-Smith, A., Williams Syndrome: From Genotype Through to the Cognitive Phenotype, Am. J. Med. Genet., 2000, vol. 97, pp. 64-71.

    Google Scholar 

  49. Okano, I., Hiraoka, J., Otera, H., et al., Identification and Characterization of a Novel Family of Serine/Threonine Kinases Containing Two N-Terminal LIM Motifs, J. Biol. Chem., 1995, vol. 270, pp. 31 321-31 330.

    Google Scholar 

  50. Ohashi, K., Hosoya, T., Takahashi, K., et al., Drosophila Homolog of LIM-Kinase Phosphorylates Cofilin and Induces Actin Cytoskeletal Reorganization, Biochem. Biophys. Res. Commun., 2000, vol. 276, pp. 1178-1185.

    Google Scholar 

  51. Wang, J.Y., Wigston, D.J., Rees, H.D., et al., LIM Kinase 1 Accumulates in Presynaptic Terminals during Synapse Maturation, J. Comp. Neurol., 2000, vol. 416, pp. 319-334.

    Google Scholar 

  52. Bailey, J.A., Yavor, A.M., Viggiano, L., et al., Human-Specific Duplication and Mosaic Transcripts: The Recent Paralogous Structure of Chromosome 22, Am. J. Hum. Genet., 2002, vol. 70, pp. 83-100.

    Google Scholar 

  53. Makunin, V., Volkova, E.I., Belyaeva, E.S., et al., The Drosophila Suppressor of Underreplication Protein Binds to Late-Replicating Regions of Polytene Chromosomes, Genetics, 2002, vol. 160, pp. 1023-1034.

    Google Scholar 

  54. Pritchard, R.H., The Linear Arrangement of a Series of Alleles of Aspergillus nidulans, Heredity, 1955, vol. 9, pp. 343-371.

    Google Scholar 

  55. Zakharov, I.A. and Inge-Vechtomov, S.G., The Effect of X-Rays and a High Temperature on Crossing Over, Issledovaniya po genetike (Studies in Genetics), 1961, vol. 1, pp. 25-37.

    Google Scholar 

  56. Marshall, W.F., Order and Disorder in the Nucleus, Curr. Biol., 2002, vol. 12, pp. 185-192.

    Google Scholar 

  57. Olave, I.A., Reck-Peterson, S., and Crabtree, G.R., Nuclear Actin and Actin-Related Proteins in Chromatin Remodeling, Annu. Rev. Biochem., 2002, vol. 71, pp. 755-781.

    Google Scholar 

  58. Ambach, A., Saunus, J., Konstandin, M., et al., The Serine Phosphatases PP1 and PP2A Associate with and Activate the Actin-Binding Protein Cofilin in Human T Lymphocytes, Eur. J. Immunol., 2000, vol. 30, pp. 3422-3431.

    Google Scholar 

  59. Asztalos, Z., von Wegerer, J., Wustmann, G., et al., Protein Phosphatase 1-Deficient Mutant of Drosophila Is Affected in Habituation and Associative Learning, J. Neurosci., 1993, vol. 13, pp. 924-930.

    Google Scholar 

  60. Baumer, A., Dutly, F., Balmer, D., et al., High Level of Unequal Meiotic Crossovers at the Origin of the 22q11.2 and 7q11.23 Deletions, Hum. Mol. Genet., 1998, vol. 7, pp. 887-894.

    Google Scholar 

  61. Fox, M.E., Yamada, T., Ohta, K., and Smith, G.R., A Family of cAMP Response Element-Related DNA Sequences with Meiotic Recombination Hotspot Activity in Schizosaccharomyces pombe, Genetics, 2000, vol. 156, pp. 59-68.

    Google Scholar 

  62. Mizuno, K., Hasemi, T., Ubukata, T., et al., Counteracting Regulation of Chromatin Remodeling at a Fission Yeast cAMP-Responsive Element-Related Recombination Hotspot by Stress-Activated Protein Kinase, cAMP-Dependent Kinase and Meiosis Regulators, Genetics, 2001, vol. 159, pp. 1467-1478.

    Google Scholar 

  63. Wada, A., Fukuda, M., Mishima, M., and Nishida, E., Nuclear Export of Actin: A Novel Mechanism Regulating the Subcellular Localization of a Major Cytoskeletal Protein, EMBO J., 1998, vol. 17, pp. 1635-1641.

    Google Scholar 

  64. Yang, N. and Mizuno, K., Nuclear Export of LIM-Kinase 1, Mediated by Two Leucine-Rich Nuclear-Export Signals within the PDZ Domain, Biochem. J., 1999, vol. 338, pp. 793-798.

    Google Scholar 

  65. Van Aelst, L. and D'Souza-Schorey, C., Rho GTPases and Signaling Networks, Genes Dev., 1997, vol. 11, pp. 2295-2322.

    Google Scholar 

  66. Calderwood, D.A., Shattil, S.J., and Ginsberg, M.H., Integrins and Actin Filaments: Reciprocal Regulation of Cell Adhesion and Signaling, J. Biol. Chem., 2000, vol. 275, pp. 22 607-22 610.

    Google Scholar 

  67. Jackson, S.M. and Berg, C.A., Soma-to-Germline Interactions during Drosophila Oogenesis Are Influenced by Dose-Sensitive Interactions between Cut and the Genes cappuccino, ovarian tumor and agnostic, Genetics, 1999, vol. 153, pp. 289-303.

    Google Scholar 

  68. Shabahang, S., Huwiler, A., and Pfeilschifter, J., Identification of the LIM Kinase-1 As a Ceramide-Regulated Gene in Renal Mesangial Cells, Biochem. Biophys. Res. Commun., 2002, vol. 298, pp. 408-413.

    Google Scholar 

  69. Geneste, O., Copeland, J.W., and Treisman, R., LIM Kinase and Diaphanous Cooperate to Regulate Serum Response Factor and Actin Dynamics, J. Cell Biol., 2002, vol. 157, pp. 831-838.

    Google Scholar 

  70. Ge'cz, J. and Mulley, J., Genes for Cognitive Function: Developments on the X, Genome Res., 2000, vol. 10, pp. 157-163.

    Google Scholar 

  71. Lobashev, M.E., Ponomarenko, V.V., Polyanskaya, G.G., and Tsapygina, R.I., On the Role of the Nervous System in Regulating a Variety of Genetic and Cytogenetic Processes, Zh. Evol. Biokhim. Fiziol., 1973, vol. 9, pp. 396-406.

    Google Scholar 

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Authors and Affiliations

  1. Pavlov Institute of Physiology, Russian Academy of Sciences, St. Petersburg, 199034, Russia

    E. V. Savvateeva-Popova, A. I. Peresleni, L. M. Scharagina, A. V. Medvedeva, S. E. Korochkina, I. V. Grigorieva & N. A. Dyuzhikova

  2. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, 194223, Russia

    A. V. Popov

  3. Institute of Cytology and Genetics, Russian Academy of Sciences, Novosibirsk, 630090, Russia

    E. M. Baricheva & D. Karagodin

  4. Theodor-Boveri-Institut für Biowissenschaften, Würzburg, 97074, Germany

    E. V. Savvateeva-Popova & M. Heisenberg

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Savvateeva-Popova, E.V., Peresleni, A.I., Scharagina, L.M. et al. Architecture of the X Chromosome, Expression of LIM Kinase 1, and Recombination in the agnostic Mutants of Drosophila: A Model for Human Williams Syndrome. Russian Journal of Genetics 40, 605–624 (2004). https://doi.org/10.1023/B:RUGE.0000033308.97306.9a

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