title: Sialyltransferase regulates nervous system function in Drosophila.
abstract: In vertebrates, sialylated glycans participate in a wide range of biological processes and affect the development and function of the nervous system. While the complexity of glycosylation and the functional redundancy among sialyltransferases provide obstacles for revealing biological roles of sialylation in mammals, Drosophila possesses a sole vertebrate-type sialyltransferase, Drosophila sialyltransferase (DSiaT), with significant homology to its mammalian counterparts, suggesting that Drosophila could be a suitable model to investigate the function of sialylation. To explore this possibility and investigate the role of sialylation in Drosophila, we inactivated DSiaT in vivo by gene targeting and analyzed phenotypes of DSiaT mutants using a combination of behavioral, immunolabeling, electrophysiological, and pharmacological approaches. Our experiments demonstrated that DSiaT expression is restricted to a subset of CNS neurons throughout development. We found that DSiaT mutations result in significantly decreased life span, locomotor abnormalities, temperature-sensitive paralysis, and defects of neuromuscular junctions. Our results indicate that DSiaT regulates neuronal excitability and affects the function of a voltage-gated sodium channel. Finally, we showed that sialyltransferase activity is required for DSiaT function in vivo, which suggests that DSiaT mutant phenotypes result from a defect in sialylation of N-glycans. This work provided the first evidence that sialylation has an important biological function in protostomes, while also revealing a novel, nervous system-specific function of alpha2,6-sialylation. Thus, our data shed light on one of the most ancient functions of sialic acids in metazoan organisms and suggest a possibility that this function is evolutionarily conserved between flies and mammals.
authors.affiliation: Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Repnikova
authors.forename: Kate
authors.initials: K
authors.lastname: Koles
authors.forename: Michiko
authors.initials: M
authors.lastname: Nakamura
authors.forename: Jared
authors.initials: J
authors.lastname: Pitts
authors.forename: Haiwen
authors.initials: H
authors.lastname: Li
authors.forename: Apoorva
authors.initials: A
authors.lastname: Ambavane
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Zoran
authors.forename: Vladislav M
authors.initials: VM
authors.lastname: Panin
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D002490:Central Nervous System / Q000033:anatomy & histology / Q000254:growth & development / Q000378:metabolism / Q000502:physiology*; D004330:Drosophila / Q000201:enzymology / Q000502:physiology; D020233:Gait Disorders, Neurologic / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D017344:Genes, Insect / Q000502:physiology; D008136:Longevity / Q000235:genetics; D009154:Mutation; D009469:Neuromuscular Junction / Q000235:genetics / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D012799:Sialyltransferases / Q000235:genetics / Q000502:physiology*; D015222:Sodium Channels / Q000235:genetics / Q000502:physiology; D055366:Synaptic Potentials / Q000235:genetics / Q000502:physiology
chemical_list: D015222:Sodium Channels; D012799:Sialyltransferases
references.citation: J Neurosci. 2008 Apr 2;28(14):3668-82
references.pmid: 18385325
references.citation: Proc Natl Acad Sci U S A. 1971 May;68(5):890-3
references.pmid: 5280526
references.citation: Biol Chem. 2009 Jul;390(7):567-74
references.pmid: 19426138
references.citation: J Neurophysiol. 2004 May;91(5):2353-65
references.pmid: 14695352
references.citation: J Neurosci. 2003 Jul 23;23(16):6546-56
references.pmid: 12878696
references.citation: J Comp Physiol A. 1994 Aug;175(2):179-91
references.pmid: 8071894
references.citation: Methods Mol Biol. 2008;420:155-74
references.pmid: 18641946
references.citation: Neuron. 1996 Oct;17(4):627-40
references.pmid: 8893021
references.citation: Neuron. 2000 Apr;26(1):13-25
references.pmid: 10798388
references.citation: J Biol Chem. 2006 Jun 9;281(23):15929-40
references.pmid: 16537535
references.citation: Bioinformatics. 2007 Nov 1;23(21):2947-8
references.pmid: 17846036
references.citation: J Biol Chem. 2004 Apr 2;279(14):13461-8
references.pmid: 14722111
references.citation: J Neurosci. 2001 Dec 15;21(24):9629-37
references.pmid: 11739573
references.citation: Genetics. 1984 Dec;108(4):897-911
references.pmid: 6096206
references.citation: Dev Biol. 2002 Aug 15;248(2):369-83
references.pmid: 12167411
references.citation: Science. 2000 Jun 16;288(5473):2013-8
references.pmid: 10856208
references.citation: J Neurochem. 2007 Nov;103 Suppl 1:56-64
references.pmid: 17986140
references.citation: J Neurosci. 2007 Oct 24;27(43):11587-94
references.pmid: 17959801
references.citation: Curr Biol. 2000 Feb 24;10(4):211-4
references.pmid: 10704417
references.citation: Eur J Biochem. 2003 Mar;270(5):950-61
references.pmid: 12603328
references.citation: Neuron. 2000 Jul;27(1):71-84
references.pmid: 10939332
references.citation: Neuron. 2006 Mar 16;49(6):833-44
references.pmid: 16543132
references.citation: J Neurosci. 1990 Nov;10(11):3754-68
references.pmid: 1700086
references.citation: J Comp Neurol. 2008 May 1;508(1):131-52
references.pmid: 18302156
references.citation: IUBMB Life. 2007 Mar;59(3):151-62
references.pmid: 17487686
references.citation: Biochim Biophys Acta. 2006 Apr;1760(4):685-92
references.pmid: 16439063
references.citation: J Neurosci. 2008 Apr 2;28(14):3781-9
references.pmid: 18385336
references.citation: Glycobiology. 2007 Dec;17(12):1388-403
references.pmid: 17893096
references.citation: Cell. 1995 Sep 22;82(6):1001-11
references.pmid: 7553842
references.citation: Proc Natl Acad Sci U S A. 1983 Aug;80(16):4949-53
references.pmid: 6192445
references.citation: Cell. 2001 Nov 16;107(4):501-12
references.pmid: 11719190
references.citation: Biochemistry. 1983 Jan 18;22(2):462-70
references.pmid: 6186277
references.citation: Proc Natl Acad Sci U S A. 2007 Aug 28;104(35):14122-7
references.pmid: 17709738
references.citation: J Biol Chem. 2001 Jul 27;276(30):28197-203
references.pmid: 11369778
references.citation: Neuron. 2005 Oct 6;48(1):91-107
references.pmid: 16202711
references.citation: J Biol Chem. 1992 May 15;267(14):9965-71
references.pmid: 1315775
references.citation: Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2556-61
references.pmid: 12589026
references.citation: Neuron. 2002 Sep 26;36(1):105-19
references.pmid: 12367510
references.citation: J Biol Chem. 2002 Sep 6;277(36):32930-8
references.pmid: 12068010
references.citation: J Biol Chem. 2004 Jul 30;279(31):32603-13
references.pmid: 15140899
references.citation: Cell. 2000 Aug 18;102(4):437-49
references.pmid: 10966106
references.citation: Insect Biochem Mol Biol. 2008 May;38(5):604-10
references.pmid: 18405837
references.citation: Curr Opin Neurobiol. 2007 Feb;17(1):35-42
references.pmid: 17229568
references.citation: J Gen Physiol. 2006 Mar;127(3):253-65
references.pmid: 16476705
references.citation: J Biol Chem. 2007 Mar 23;282(12):9127-42
references.pmid: 17264077
references.citation: J Neurosci. 2000 Jul 15;20(14):5234-44
references.pmid: 10884307
references.citation: J Biol Chem. 1987 Feb 15;262(5):2298-303
references.pmid: 2434481
references.citation: Genetics. 2008 Feb;178(2):947-56
references.pmid: 18245348
references.citation: J Neurosci. 1997 Nov 1;17(21):8137-46
references.pmid: 9334389
references.citation: Annu Rev Physiol. 2002;64:355-405
references.pmid: 11826273
references.citation: Genetics. 2006 Jan;172(1):343-53
references.pmid: 16219785
references.citation: Nature. 2001 May 24;411(6836):476-80
references.pmid: 11373680
references.citation: Chem Rev. 2002 Feb;102(2):439-69
references.pmid: 11841250
references.citation: J Biol Chem. 2004 Feb 6;279(6):4346-57
references.pmid: 14612445
references.citation: J Neurophysiol. 2005 Sep;94(3):1888-903
references.pmid: 15888532
references.citation: Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4504-9
references.pmid: 9539767
references.citation: Neuron. 1996 Sep;17(3):413-22
references.pmid: 8816705
references.citation: J Neurogenet. 1997 Nov;11(3-4):231-54
references.pmid: 10876655
references.citation: Biol Chem. 2001 Feb;382(2):151-9
references.pmid: 11308014
references.citation: Genetics. 2006 Feb;172(2):1031-42
references.pmid: 16272407
references.citation: Science. 2006 May 19;312(5776):1051-4
references.pmid: 16614170
references.citation: J Cell Biol. 2007 Jul 16;178(2):309-22
references.pmid: 17620409
references.citation: Cell. 1989 Sep 22;58(6):1143-54
references.pmid: 2550145
references.citation: Biochem Biophys Res Commun. 1987 Oct 29;148(2):817-26
references.pmid: 2446601
references.citation: Neuron. 1990 Nov;5(5):675-84
references.pmid: 2171591
references.citation: Biochimie. 2001 Aug;83(8):727-37
references.pmid: 11530204
references.citation: Nat Rev Neurosci. 2007 Jun;8(6):451-65
references.pmid: 17514198
references.citation: Trends Mol Med. 2008 Aug;14(8):351-60
references.pmid: 18606570
references.citation: Genetics. 2003 May;164(1):163-71
references.pmid: 12750329
references.citation: J Biol Chem. 2002 Nov 29;277(48):45719-28
references.pmid: 12235148
references.citation: Genetics. 2007 Feb;175(2):671-9
references.pmid: 17151241
references.citation: Proc Natl Acad Sci U S A. 1982 Apr;79(8):2700-4
references.pmid: 6806816
references.citation: J Biol Chem. 1987 Oct 5;262(28):13713-23
references.pmid: 2443496
references.citation: Nature. 2007 Apr 26;446(7139):1023-9
references.pmid: 17460663
references.citation: Cell. 2002 Apr 5;109(1):101-12
references.pmid: 11955450
references.citation: J Neurosci. 2002 Jul 15;22(14):5856-64
references.pmid: 12122048
references.citation: J Cell Biol. 2000 Nov 13;151(4):905-18
references.pmid: 11076973
references.citation: J Physiol. 2002 Feb 1;538(Pt 3):675-90
references.pmid: 11826157
references.citation: Genetics. 2004 Nov;168(3):1467-76
references.pmid: 15579699
references.citation: Mol Gen Genet. 1997 Nov;256(6):602-10
references.pmid: 9435785
references.citation: Neuron. 2003 Nov 13;40(4):733-48
references.pmid: 14622578
references.citation: J Biol Chem. 2002 Aug 16;277(33):29945-52
references.pmid: 12036964
references.citation: J Neurobiol. 2004 Dec;61(3):392-9
references.pmid: 15490479
references.citation: Nat Neurosci. 1999 Nov;2(11):965-71
references.pmid: 10526334
references.citation: Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13955-60
references.pmid: 11095753
references.citation: Nat Rev Neurosci. 2008 Jan;9(1):26-35
references.pmid: 18059411
references.citation: Glycobiology. 2002 Feb;12(2):73-83
references.pmid: 11886840
references.citation: Nature. 1967 Jul 1;215(5096):57-8
references.pmid: 4293258
references.citation: Cancer Res. 2008 Jan 15;68(2):388-94
references.pmid: 18199532
references.citation: J Biol Chem. 2001 May 11;276(19):15696-703
references.pmid: 11278664
references.citation: J Neurosci. 2004 Feb 11;24(6):1439-45
references.pmid: 14960616
references.citation: Genetics. 2002 Jul;161(3):1197-208
references.pmid: 12136022
references.citation: Glycoconj J. 2009 Apr;26(3):313-24
references.pmid: 18568399
references.citation: J Physiol. 1968 Mar;195(2):481-92
references.pmid: 4296699
references.citation: Sci STKE. 2002 Apr 30;2002(130):pe19
references.pmid: 11983936