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. 2002 Nov;162(3):1283–1299. doi: 10.1093/genetics/162.3.1283

The Drosophila slamdance gene: a mutation in an aminopeptidase can cause seizure, paralysis and neuronal failure.

HaiGuang Zhang 1, Jeff Tan 1, Elaine Reynolds 1, Daniel Kuebler 1, Sally Faulhaber 1, Mark Tanouye 1
PMCID: PMC1462322  PMID: 12454073

Abstract

We report here the characterization of slamdance (sda), a Drosophila melanogaster "bang-sensitive" (BS) paralytic mutant. This mutant exhibits hyperactive behavior and paralysis following a mechanical "bang" or electrical shock. Electrophysiological analyses have shown that this mutant is much more prone to seizure episodes than normal flies because it has a drastically lowered seizure threshold. Through genetic mapping, molecular cloning, and RNA interference, we have demonstrated that the sda phenotype can be attributed to a mutation in the Drosophila homolog of the human aminopeptidase N (APN) gene. Furthermore, using mRNA in situ hybridization and LacZ staining, we have found that the sda gene is expressed specifically in the central nervous system at particular developmental stages. Together, these results suggest that the bang sensitivity in sda mutants is caused by a defective APN gene that somehow increases seizure susceptibility. Finally, by using the sda mutation as a sensitized background, we have been able to identify a rich variety of sda enhancers and other independent BS mutations.

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Selected References

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  1. Aigner L., Arber S., Kapfhammer J. P., Laux T., Schneider C., Botteri F., Brenner H. R., Caroni P. Overexpression of the neural growth-associated protein GAP-43 induces nerve sprouting in the adult nervous system of transgenic mice. Cell. 1995 Oct 20;83(2):269–278. doi: 10.1016/0092-8674(95)90168-x. [DOI] [PubMed] [Google Scholar]
  2. Amoscato A. A., Alexander J. W., Babcock G. F. Surface aminopeptidase activity of human lymphocytes. I. Biochemical and biologic properties of intact cells. J Immunol. 1989 Feb 15;142(4):1245–1252. [PubMed] [Google Scholar]
  3. Baraban S. C., Hollopeter G., Erickson J. C., Schwartzkroin P. A., Palmiter R. D. Knock-out mice reveal a critical antiepileptic role for neuropeptide Y. J Neurosci. 1997 Dec 1;17(23):8927–8936. doi: 10.1523/JNEUROSCI.17-23-08927.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Benzer S. From the gene to behavior. JAMA. 1971 Nov 15;218(7):1015–1022. [PubMed] [Google Scholar]
  5. Burgess D. L., Jones J. M., Meisler M. H., Noebels J. L. Mutation of the Ca2+ channel beta subunit gene Cchb4 is associated with ataxia and seizures in the lethargic (lh) mouse. Cell. 1997 Feb 7;88(3):385–392. doi: 10.1016/s0092-8674(00)81877-2. [DOI] [PubMed] [Google Scholar]
  6. Butler L. S., Silva A. J., Abeliovich A., Watanabe Y., Tonegawa S., McNamara J. O. Limbic epilepsy in transgenic mice carrying a Ca2+/calmodulin-dependent kinase II alpha-subunit mutation. Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):6852–6855. doi: 10.1073/pnas.92.15.6852. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cadel S., Foulon T., Viron A., Balogh A., Midol-Monnet S., Noël N., Cohen P. Aminopeptidase B from the rat testis is a bifunctional enzyme structurally related to leukotriene-A4 hydrolase. Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):2963–2968. doi: 10.1073/pnas.94.7.2963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Carthew R. W. Gene silencing by double-stranded RNA. Curr Opin Cell Biol. 2001 Apr;13(2):244–248. doi: 10.1016/s0955-0674(00)00204-0. [DOI] [PubMed] [Google Scholar]
  9. Constam D. B., Tobler A. R., Rensing-Ehl A., Kemler I., Hersh L. B., Fontana A. Puromycin-sensitive aminopeptidase. Sequence analysis, expression, and functional characterization. J Biol Chem. 1995 Nov 10;270(45):26931–26939. doi: 10.1074/jbc.270.45.26931. [DOI] [PubMed] [Google Scholar]
  10. Delmas B., Gelfi J., Kut E., Sjöström H., Noren O., Laude H. Determinants essential for the transmissible gastroenteritis virus-receptor interaction reside within a domain of aminopeptidase-N that is distinct from the enzymatic site. J Virol. 1994 Aug;68(8):5216–5224. doi: 10.1128/jvi.68.8.5216-5224.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Delmas B., Gelfi J., L'Haridon R., Vogel L. K., Sjöström H., Norén O., Laude H. Aminopeptidase N is a major receptor for the entero-pathogenic coronavirus TGEV. Nature. 1992 Jun 4;357(6377):417–420. doi: 10.1038/357417a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Ekşioğlu Y. Z., Scheffer I. E., Cardenas P., Knoll J., DiMario F., Ramsby G., Berg M., Kamuro K., Berkovic S. F., Duyk G. M. Periventricular heterotopia: an X-linked dominant epilepsy locus causing aberrant cerebral cortical development. Neuron. 1996 Jan;16(1):77–87. doi: 10.1016/s0896-6273(00)80025-2. [DOI] [PubMed] [Google Scholar]
  13. Falk K., Rötzschke O., Stevanović S., Jung G., Rammensee H. G. Pool sequencing of natural HLA-DR, DQ, and DP ligands reveals detailed peptide motifs, constraints of processing, and general rules. Immunogenetics. 1994;39(4):230–242. doi: 10.1007/BF00188785. [DOI] [PubMed] [Google Scholar]
  14. Fletcher C. F., Lutz C. M., O'Sullivan T. N., Shaughnessy J. D., Jr, Hawkes R., Frankel W. N., Copeland N. G., Jenkins N. A. Absence epilepsy in tottering mutant mice is associated with calcium channel defects. Cell. 1996 Nov 15;87(4):607–617. doi: 10.1016/s0092-8674(00)81381-1. [DOI] [PubMed] [Google Scholar]
  15. Fox J. W., Lamperti E. D., Ekşioğlu Y. Z., Hong S. E., Feng Y., Graham D. A., Scheffer I. E., Dobyns W. B., Hirsch B. A., Radtke R. A. Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia. Neuron. 1998 Dec;21(6):1315–1325. doi: 10.1016/s0896-6273(00)80651-0. [DOI] [PubMed] [Google Scholar]
  16. Fukasawa K. M., Fukasawa K., Kanai M., Fujii S., Harada M. Molecular cloning and expression of rat liver aminopeptidase B. J Biol Chem. 1996 Nov 29;271(48):30731–30735. doi: 10.1074/jbc.271.48.30731. [DOI] [PubMed] [Google Scholar]
  17. Ishii K., Usui S., Sugimura Y., Yoshida S., Hioki T., Tatematsu M., Yamamoto H., Hirano K. Aminopeptidase N regulated by zinc in human prostate participates in tumor cell invasion. Int J Cancer. 2001 Apr 1;92(1):49–54. [PubMed] [Google Scholar]
  18. Kamb A., Iverson L. E., Tanouye M. A. Molecular characterization of Shaker, a Drosophila gene that encodes a potassium channel. Cell. 1987 Jul 31;50(3):405–413. doi: 10.1016/0092-8674(87)90494-6. [DOI] [PubMed] [Google Scholar]
  19. Keller S. R., Scott H. M., Mastick C. C., Aebersold R., Lienhard G. E. Cloning and characterization of a novel insulin-regulated membrane aminopeptidase from Glut4 vesicles. J Biol Chem. 1995 Oct 6;270(40):23612–23618. doi: 10.1074/jbc.270.40.23612. [DOI] [PubMed] [Google Scholar]
  20. Kennerdell J. R., Carthew R. W. Use of dsRNA-mediated genetic interference to demonstrate that frizzled and frizzled 2 act in the wingless pathway. Cell. 1998 Dec 23;95(7):1017–1026. doi: 10.1016/s0092-8674(00)81725-0. [DOI] [PubMed] [Google Scholar]
  21. Kido A., Krueger S., Haeckel C., Roessner A. Possible contribution of aminopeptidase N (APN/CD13) to invasive potential enhanced by interleukin-6 and soluble interleukin-6 receptor in human osteosarcoma cell lines. Clin Exp Metastasis. 1999;17(10):857–863. doi: 10.1023/a:1006794617406. [DOI] [PubMed] [Google Scholar]
  22. Koch A. E., Burrows J. C., Skoutelis A., Marder R., Domer P. H., Anderson B., Leibovich S. J. Monoclonal antibodies detect monocyte/macrophage activation and differentiation antigens and identify functionally distinct subpopulations of human rheumatoid synovial tissue macrophages. Am J Pathol. 1991 Jan;138(1):165–173. [PMC free article] [PubMed] [Google Scholar]
  23. Kopczynski C. C., Noordermeer J. N., Serano T. L., Chen W. Y., Pendleton J. D., Lewis S., Goodman C. S., Rubin G. M. A high throughput screen to identify secreted and transmembrane proteins involved in Drosophila embryogenesis. Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):9973–9978. doi: 10.1073/pnas.95.17.9973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kuebler D., Zhang H., Ren X., Tanouye M. A. Genetic suppression of seizure susceptibility in Drosophila. J Neurophysiol. 2001 Sep;86(3):1211–1225. doi: 10.1152/jn.2001.86.3.1211. [DOI] [PubMed] [Google Scholar]
  25. Letts V. A., Felix R., Biddlecome G. H., Arikkath J., Mahaffey C. L., Valenzuela A., Bartlett F. S., 2nd, Mori Y., Campbell K. P., Frankel W. N. The mouse stargazer gene encodes a neuronal Ca2+-channel gamma subunit. Nat Genet. 1998 Aug;19(4):340–347. doi: 10.1038/1228. [DOI] [PubMed] [Google Scholar]
  26. Look A. T., Ashmun R. A., Shapiro L. H., Peiper S. C. Human myeloid plasma membrane glycoprotein CD13 (gp150) is identical to aminopeptidase N. J Clin Invest. 1989 Apr;83(4):1299–1307. doi: 10.1172/JCI114015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Luciani N., Marie-Claire C., Ruffet E., Beaumont A., Roques B. P., Fournié-Zaluski M. C. Characterization of Glu350 as a critical residue involved in the N-terminal amine binding site of aminopeptidase N (EC 3.4.11.2): insights into its mechanism of action. Biochemistry. 1998 Jan 13;37(2):686–692. doi: 10.1021/bi971705p. [DOI] [PubMed] [Google Scholar]
  28. Mazzocco C., Fukasawa K. M., Raymond A. A., Puiroux J. Purification, partial sequencing and characterization of an insect membrane dipeptidyl aminopeptidase that degrades the insect neuropeptide proctolin. Eur J Biochem. 2001 Sep;268(18):4940–4949. doi: 10.1046/j.1432-1327.2001.02425.x. [DOI] [PubMed] [Google Scholar]
  29. McCaman M. T., Gabe J. D. Sequence of the promoter and 5' coding region of pepN, and the amino-terminus of peptidase N from Escherichia coli K-12. Mol Gen Genet. 1986 Jul;204(1):148–152. doi: 10.1007/BF00330202. [DOI] [PubMed] [Google Scholar]
  30. Montiel J. L., Cornille F., Roques B. P., Noble F. Nociceptin/orphanin FQ metabolism: role of aminopeptidase and endopeptidase 24.15. J Neurochem. 1997 Jan;68(1):354–361. doi: 10.1046/j.1471-4159.1997.68010354.x. [DOI] [PubMed] [Google Scholar]
  31. Nanus D. M., Engelstein D., Gastl G. A., Gluck L., Vidal M. J., Morrison M., Finstad C. L., Bander N. H., Albino A. P. Molecular cloning of the human kidney differentiation antigen gp160: human aminopeptidase A. Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):7069–7073. doi: 10.1073/pnas.90.15.7069. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Olsen J., Cowell G. M., Kønigshøfer E., Danielsen E. M., Møller J., Laustsen L., Hansen O. C., Welinder K. G., Engberg J., Hunziker W. Complete amino acid sequence of human intestinal aminopeptidase N as deduced from cloned cDNA. FEBS Lett. 1988 Oct 10;238(2):307–314. doi: 10.1016/0014-5793(88)80502-7. [DOI] [PubMed] [Google Scholar]
  33. Pavlidis P., Ramaswami M., Tanouye M. A. The Drosophila easily shocked gene: a mutation in a phospholipid synthetic pathway causes seizure, neuronal failure, and paralysis. Cell. 1994 Oct 7;79(1):23–33. doi: 10.1016/0092-8674(94)90397-2. [DOI] [PubMed] [Google Scholar]
  34. Pavlidis P., Tanouye M. A. Seizures and failures in the giant fiber pathway of Drosophila bang-sensitive paralytic mutants. J Neurosci. 1995 Aug;15(8):5810–5819. doi: 10.1523/JNEUROSCI.15-08-05810.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Rawlings N. D., Barrett A. J. Families of aspartic peptidases, and those of unknown catalytic mechanism. Methods Enzymol. 1995;248:105–120. doi: 10.1016/0076-6879(95)48009-9. [DOI] [PubMed] [Google Scholar]
  36. Riemann D., Kehlen A., Langner J. CD13--not just a marker in leukemia typing. Immunol Today. 1999 Feb;20(2):83–88. doi: 10.1016/S0167-5699(98)01398-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Rosahl T. W., Spillane D., Missler M., Herz J., Selig D. K., Wolff J. R., Hammer R. E., Malenka R. C., Südhof T. C. Essential functions of synapsins I and II in synaptic vesicle regulation. Nature. 1995 Jun 8;375(6531):488–493. doi: 10.1038/375488a0. [DOI] [PubMed] [Google Scholar]
  38. Royden C. S., Pirrotta V., Jan L. Y. The tko locus, site of a behavioral mutation in D. melanogaster, codes for a protein homologous to prokaryotic ribosomal protein S12. Cell. 1987 Oct 23;51(2):165–173. doi: 10.1016/0092-8674(87)90144-9. [DOI] [PubMed] [Google Scholar]
  39. Saiki I., Fujii H., Yoneda J., Abe F., Nakajima M., Tsuruo T., Azuma I. Role of aminopeptidase N (CD13) in tumor-cell invasion and extracellular matrix degradation. Int J Cancer. 1993 Apr 22;54(1):137–143. doi: 10.1002/ijc.2910540122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Sanderink G. J., Artur Y., Siest G. Human aminopeptidases: a review of the literature. J Clin Chem Clin Biochem. 1988 Dec;26(12):795–807. doi: 10.1515/cclm.1988.26.12.795. [DOI] [PubMed] [Google Scholar]
  41. Santos A. N., Langner J., Herrmann M., Riemann D. Aminopeptidase N/CD13 is directly linked to signal transduction pathways in monocytes. Cell Immunol. 2000 Apr 10;201(1):22–32. doi: 10.1006/cimm.2000.1629. [DOI] [PubMed] [Google Scholar]
  42. Schauder B., Schomburg L., Köhrle J., Bauer K. Cloning of a cDNA encoding an ectoenzyme that degrades thyrotropin-releasing hormone. Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9534–9538. doi: 10.1073/pnas.91.20.9534. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Shipp M. A., Look A. T. Hematopoietic differentiation antigens that are membrane-associated enzymes: cutting is the key! Blood. 1993 Aug 15;82(4):1052–1070. [PubMed] [Google Scholar]
  44. Solhonne B., Gros C., Pollard H., Schwartz J. C. Major localization of aminopeptidase M in rat brain microvessels. Neuroscience. 1987 Jul;22(1):225–232. doi: 10.1016/0306-4522(87)90212-0. [DOI] [PubMed] [Google Scholar]
  45. Tanouye M. A., Wyman R. J. Motor outputs of giant nerve fiber in Drosophila. J Neurophysiol. 1980 Aug;44(2):405–421. doi: 10.1152/jn.1980.44.2.405. [DOI] [PubMed] [Google Scholar]
  46. Taylor A. Aminopeptidases: structure and function. FASEB J. 1993 Feb 1;7(2):290–298. doi: 10.1096/fasebj.7.2.8440407. [DOI] [PubMed] [Google Scholar]
  47. Ward P. E., Benter I. F., Dick L., Wilk S. Metabolism of vasoactive peptides by plasma and purified renal aminopeptidase M. Biochem Pharmacol. 1990 Oct 15;40(8):1725–1732. doi: 10.1016/0006-2952(90)90348-o. [DOI] [PubMed] [Google Scholar]
  48. Watt V. M., Willard H. F. The human aminopeptidase N gene: isolation, chromosome localization, and DNA polymorphism analysis. Hum Genet. 1990 Oct;85(6):651–654. doi: 10.1007/BF00193592. [DOI] [PubMed] [Google Scholar]
  49. Wu C. F., Ganetzky B. Neurogenetic studies of ion channels in Drosophila. Ion Channels. 1992;3:261–314. doi: 10.1007/978-1-4615-3328-3_9. [DOI] [PubMed] [Google Scholar]
  50. Yeager C. L., Ashmun R. A., Williams R. K., Cardellichio C. B., Shapiro L. H., Look A. T., Holmes K. V. Human aminopeptidase N is a receptor for human coronavirus 229E. Nature. 1992 Jun 4;357(6377):420–422. doi: 10.1038/357420a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Zini S., Fournie-Zaluski M. C., Chauvel E., Roques B. P., Corvol P., Llorens-Cortes C. Identification of metabolic pathways of brain angiotensin II and III using specific aminopeptidase inhibitors: predominant role of angiotensin III in the control of vasopressin release. Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11968–11973. doi: 10.1073/pnas.93.21.11968. [DOI] [PMC free article] [PubMed] [Google Scholar]

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