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. 1999 Sep;153(1):361–382. doi: 10.1093/genetics/153.1.361

The catecholamines up (Catsup) protein of Drosophila melanogaster functions as a negative regulator of tyrosine hydroxylase activity.

D G Stathakis 1, D Y Burton 1, W E McIvor 1, S Krishnakumar 1, T R Wright 1, J M O'Donnell 1
PMCID: PMC1460756  PMID: 10471719

Abstract

We report the genetic, phenotypic, and biochemical analyses of Catecholamines up (Catsup), a gene that encodes a negative regulator of tyrosine hydroxylase (TH) activity. Mutations within this locus are semidominant lethals of variable penetrance that result in three broad, overlapping effective lethal phases (ELPs), indicating that the Catsup gene product is essential throughout development. Mutants from each ELP exhibit either cuticle defects or catecholamine-related abnormalities, such as melanotic salivary glands or pseudotumors. Additionally, Catsup mutants have significantly elevated TH activity that may arise from a post-translational modification of the enzyme. The hyperactivation of TH in Catsup mutants results in abnormally high levels of catecholamines, which can account for the lethality, visible phenotypes, and female sterility observed in these mutants. We propose that Catsup is a component of a novel system that downregulates TH activity, making Catsup the fourth locus found within the Dopa decarboxylase (Ddc) gene cluster that functions in catecholamine metabolism.

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Selected References

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  1. Abou-Donia M. M., Wilson S. P., Zimmerman T. P., Nichol C. A., Viveros O. H. Regulation of guanosine triphosphate cyclohydrolase and tetrahydrobiopterin levels and the role of the cofactor in tyrosine hydroxylation in primary cultures of adrenomedullary chromaffin cells. J Neurochem. 1986 Apr;46(4):1190–1199. doi: 10.1111/j.1471-4159.1986.tb00637.x. [DOI] [PubMed] [Google Scholar]
  2. Beltrami E., Jesty J. Mathematical analysis of activation thresholds in enzyme-catalyzed positive feedbacks: application to the feedbacks of blood coagulation. Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8744–8748. doi: 10.1073/pnas.92.19.8744. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Birman S., Morgan B., Anzivino M., Hirsh J. A novel and major isoform of tyrosine hydroxylase in Drosophila is generated by alternative RNA processing. J Biol Chem. 1994 Oct 21;269(42):26559–26567. [PubMed] [Google Scholar]
  4. Black B. C., Pentz E. S., Wright T. R. The alpha methyl dopa hypersensitive gene, 1(2)amd, and two adjacent genes in Drosophila melanogaster: physical location and direct effects of amd on catecholamine metabolism. Mol Gen Genet. 1987 Sep;209(2):306–312. doi: 10.1007/BF00329658. [DOI] [PubMed] [Google Scholar]
  5. Church G. M., Gilbert W. Genomic sequencing. Proc Natl Acad Sci U S A. 1984 Apr;81(7):1991–1995. doi: 10.1073/pnas.81.7.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Eveleth D. D., Marsh J. L. Evidence for evolutionary duplication of genes in the dopa decarboxylase region of Drosophila. Genetics. 1986 Oct;114(2):469–483. doi: 10.1093/genetics/114.2.469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fillenz M. Short-term control of transmitter synthesis in central catecholaminergic neurones. Prog Biophys Mol Biol. 1993;60(1):29–46. doi: 10.1016/0079-6107(93)90011-8. [DOI] [PubMed] [Google Scholar]
  8. Fujimoto K., Okino N., Kawabata S., Iwanaga S., Ohnishi E. Nucleotide sequence of the cDNA encoding the proenzyme of phenol oxidase A1 of Drosophila melanogaster. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7769–7773. doi: 10.1073/pnas.92.17.7769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gahn L. G., Roskoski R., Jr Thermal stability and CD analysis of rat tyrosine hydroxylase. Biochemistry. 1995 Jan 10;34(1):252–256. doi: 10.1021/bi00001a030. [DOI] [PubMed] [Google Scholar]
  10. Kawamura M., Kominami K., Takeuchi J., Toh-e A. A multicopy suppressor of nin1-1 of the yeast Saccharomyces cerevisiae is a counterpart of the Drosophila melanogaster diphenol oxidase A2 gene, Dox-A2. Mol Gen Genet. 1996 May 23;251(2):146–152. doi: 10.1007/BF02172912. [DOI] [PubMed] [Google Scholar]
  11. Konrad K. D., Wang D., Marsh J. L. Vitelline membrane biogenesis in Drosophila requires the activity of the alpha-methyl dopa hypersensitive gene (I(2)amd) in both the germline and follicle cells. Insect Mol Biol. 1993;1(4):179–187. doi: 10.1111/j.1365-2583.1993.tb00090.x. [DOI] [PubMed] [Google Scholar]
  12. Kumer S. C., Vrana K. E. Intricate regulation of tyrosine hydroxylase activity and gene expression. J Neurochem. 1996 Aug;67(2):443–462. doi: 10.1046/j.1471-4159.1996.67020443.x. [DOI] [PubMed] [Google Scholar]
  13. Lapize C., Plüss C., Werner E. R., Huwiler A., Pfeilschifter J. Protein kinase C phosphorylates and activates GTP cyclohydrolase I in rat renal mesangial cells. Biochem Biophys Res Commun. 1998 Oct 29;251(3):802–805. doi: 10.1006/bbrc.1998.9552. [DOI] [PubMed] [Google Scholar]
  14. Lazar M. A., Truscott R. J., Raese J. D., Barchas J. D. Thermal denaturation of native striatal tyrosine hydroxylase: increased thermolability of the phosphorylated form of the enzyme. J Neurochem. 1981 Feb;36(2):677–682. doi: 10.1111/j.1471-4159.1981.tb01641.x. [DOI] [PubMed] [Google Scholar]
  15. McLean J. R., Krishnakumar S., O'Donnell J. M. Multiple mRNAs from the Punch locus of Drosophila melanogaster encode isoforms of GTP cyclohydrolase I with distinct N-terminal domains. J Biol Chem. 1993 Dec 25;268(36):27191–27197. [PubMed] [Google Scholar]
  16. Monastirioti M., Linn C. E., Jr, White K. Characterization of Drosophila tyramine beta-hydroxylase gene and isolation of mutant flies lacking octopamine. J Neurosci. 1996 Jun 15;16(12):3900–3911. doi: 10.1523/JNEUROSCI.16-12-03900.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. NAGATSU T., LEVITT M., UDENFRIEND S. TYROSINE HYDROXYLASE. THE INITIAL STEP IN NOREPINEPHRINE BIOSYNTHESIS. J Biol Chem. 1964 Sep;239:2910–2917. [PubMed] [Google Scholar]
  18. Neckameyer W. S. Multiple roles for dopamine in Drosophila development. Dev Biol. 1996 Jun 15;176(2):209–219. doi: 10.1006/dbio.1996.0128. [DOI] [PubMed] [Google Scholar]
  19. Neckameyer W. S., Quinn W. G. Isolation and characterization of the gene for Drosophila tyrosine hydroxylase. Neuron. 1989 Feb;2(2):1167–1175. doi: 10.1016/0896-6273(89)90183-9. [DOI] [PubMed] [Google Scholar]
  20. O'Donnell J. M., McLean J. R., Reynolds E. R. Molecular and developmental genetics of the Punch locus, a pterin biosynthesis gene in Drosophila melanogaster. Dev Genet. 1989;10(3):273–286. doi: 10.1002/dvg.1020100316. [DOI] [PubMed] [Google Scholar]
  21. Pentz E. S., Black B. C., Wright T. R. A diphenol oxidase gene is part of a cluster of genes involved in catecholamine metabolism and sclerotization in drosophila. I. Identification of the biochemical defect in Dox-A2 [l(2)37Bf] mutants. Genetics. 1986 Apr;112(4):823–841. doi: 10.1093/genetics/112.4.823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Perrimon N., Engstrom L., Mahowald A. P. The effects of zygotic lethal mutations on female germ-line functions in Drosophila. Dev Biol. 1984 Oct;105(2):404–414. doi: 10.1016/0012-1606(84)90297-5. [DOI] [PubMed] [Google Scholar]
  23. Perrimon N., Engstrom L., Mahowald A. P. Zygotic lethals with specific maternal effect phenotypes in Drosophila melanogaster. I. Loci on the X chromosome. Genetics. 1989 Feb;121(2):333–352. doi: 10.1093/genetics/121.2.333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Perrimon N., Gans M. Clonal analysis of the tissue specificity of recessive female-sterile mutations of Drosophila melanogaster using a dominant female-sterile mutation Fs(1)K1237. Dev Biol. 1983 Dec;100(2):365–373. doi: 10.1016/0012-1606(83)90231-2. [DOI] [PubMed] [Google Scholar]
  25. Reed K. C., Mann D. A. Rapid transfer of DNA from agarose gels to nylon membranes. Nucleic Acids Res. 1985 Oct 25;13(20):7207–7221. doi: 10.1093/nar/13.20.7207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Roter A. H., Spofford J. B., Swift H. Synthesis of the major adult cuticle proteins of Drosophila melanogaster during hypoderm differentiation. Dev Biol. 1985 Feb;107(2):420–431. doi: 10.1016/0012-1606(85)90324-0. [DOI] [PubMed] [Google Scholar]
  27. Spradling A. C., Stern D. M., Kiss I., Roote J., Laverty T., Rubin G. M. Gene disruptions using P transposable elements: an integral component of the Drosophila genome project. Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):10824–10830. doi: 10.1073/pnas.92.24.10824. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Stathakis D. G., Pentz E. S., Freeman M. E., Kullman J., Hankins G. R., Pearlson N. J., Wright T. R. The genetic and molecular organization of the Dopa decarboxylase gene cluster of Drosophila melanogaster. Genetics. 1995 Oct;141(2):629–655. doi: 10.1093/genetics/141.2.629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Sugumaran M., Giglio L., Kundzicz H., Saul S., Semensi V. Studies on the enzymes involved in puparial cuticle sclerotization in Drosophila melanogaster. Arch Insect Biochem Physiol. 1992;19(4):271–283. doi: 10.1002/arch.940190406. [DOI] [PubMed] [Google Scholar]
  30. Wang D., Marsh J. L. Developmental regulation of the alpha-methyldopa hypersensitive gene of Drosophila melanogaster. Dev Biol. 1995 Apr;168(2):598–612. doi: 10.1006/dbio.1995.1105. [DOI] [PubMed] [Google Scholar]
  31. Wright T. R., Bewley G. C., Sherald A. F. The genetics of dopa decarboxylase in Drosophila melanogaster. II. Isolation and characterization of dopa-decarboxylase-deficient mutants and their relationship to the alpha-methyl-dopa-hypersensitive mutants. Genetics. 1976 Oct;84(2):287–310. doi: 10.1093/genetics/84.2.287. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Wright T. R. The Wilhelmine E. Key 1992 Invitational lecture. Phenotypic analysis of the Dopa decarboxylase gene cluster mutants in Drosophila melanogaster. J Hered. 1996 May-Jun;87(3):175–190. doi: 10.1093/oxfordjournals.jhered.a022983. [DOI] [PubMed] [Google Scholar]
  33. Wright T. R. The genetics of biogenic amine metabolism, sclerotization, and melanization in Drosophila melanogaster. Adv Genet. 1987;24:127–222. [PubMed] [Google Scholar]

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