title: Complex cooperative functions of heparan sulfate proteoglycans shape nervous system development in Caenorhabditis elegans.
abstract: The development of the nervous system is a complex process requiring the integration of numerous molecular cues to form functional circuits. Many cues are regulated by heparan sulfates, a class of linear glycosaminoglycan polysaccharides. These sugars contain distinct modification patterns that regulate protein-protein interactions. Misexpressing the homolog of KAL-1/anosmin-1, a neural cell adhesion molecule mutant in Kallmann syndrome, in Caenorhabditis elegans causes a highly penetrant, heparan sulfate-dependent axonal branching phenotype in AIY interneurons. In an extended forward genetic screen for modifiers of this phenotype, we identified alleles in new as well as previously identified genes involved in HS biosynthesis and modification, namely the xylosyltransferase sqv-6, the HS-6-O-sulfotransferase hst-6, and the HS-3-O-sulfotransferase hst-3.2. Cell-specific rescue experiments showed that different HS biosynthetic and modification enzymes can be provided cell-nonautonomously by different tissues to allow kal-1-dependent branching of AIY. In addition, we show that heparan sulfate proteoglycan core proteins that carry the heparan sulfate chains act genetically in a highly redundant fashion to mediate kal-1-dependent branching in AIY neurons. Specifically, lon-2/glypican and unc-52/perlecan act in parallel genetic pathways and display synergistic interactions with sdn-1/syndecan to mediate kal-1 function. Because all of these heparan sulfate core proteins have been shown to act in different tissues, these studies indicate that KAL-1/anosmin-1 requires heparan sulfate with distinct modification patterns of different cellular origin for function. Our results support a model in which a three-dimensional scaffold of heparan sulfate mediates KAL-1/anosmin-1 and intercellular communication through complex and cooperative interactions. In addition, the genes we have identified could contribute to the etiology of Kallmann syndrome in humans.
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, 10461.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Díaz-Balzac
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, 10461.
authors.forename: María I
authors.initials: MI
authors.lastname: Lázaro-Peña
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, 10461.
authors.forename: Eillen
authors.initials: E
authors.lastname: Tecle
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, 10461.
authors.forename: Nathali
authors.initials: N
authors.lastname: Gomez
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, 10461 Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, 10461 hannes.buelow@einstein.yu.edu.
authors.forename: Hannes E
authors.identifier: http://orcid.org/0000-0002-6271-0572
authors.initials: HE
authors.lastname: Bülow
mesh_terms: D000483:Alleles; D000818:Animals; D017173:Caenorhabditis elegans / Q000254:growth & development*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D053673:Glypicans / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000737:chemistry / Q000378:metabolism*; D007395:Interneurons / Q000378:metabolism; D017436:Kallmann Syndrome / Q000473:pathology / Q000662:veterinary; D008565:Membrane Proteins / Q000378:metabolism; D016296:Mutagenesis; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009420:Nervous System / Q000378:metabolism*; D010430:Pentosyltransferases / Q000235:genetics / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism; D000097608:UDP Xylose-Protein Xylosyltransferase
chemical_list: D029742:Caenorhabditis elegans Proteins; D053673:Glypicans; D019812:Heparan Sulfate Proteoglycans; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010430:Pentosyltransferases; D011509:Proteoglycans; D015238:Sulfotransferases; D000097608:UDP Xylose-Protein Xylosyltransferase; C513487:KAL-1 protein, C elegans; C518316:LON-2 protein, C elegans; C082396:unc-52 protein, C elegans
keywords: C. elegans; Kallmann syndrome; development; heparan; nervous system
references.citation: J Biol Chem. 2009 Oct 23;284(43):29905-20
references.pmid: 19696444
references.citation: J Biol Chem. 1998 Sep 25;273(39):24979-82
references.pmid: 9737951
references.citation: Histochem Cell Biol. 2008 Oct;130(4):635-53
references.pmid: 18696101
references.citation: Mol Cell Neurosci. 2008 Jan;37(1):56-68
references.pmid: 17933550
references.citation: Nature. 1991 Oct 10;353(6344):529-36
references.pmid: 1922361
references.citation: Cell. 1991 Oct 18;67(2):423-35
references.pmid: 1913827
references.citation: J Biol Chem. 1998 Apr 10;273(15):9208-13
references.pmid: 9535912
references.citation: J Clin Invest. 2001 Jul;108(2):169-73
references.pmid: 11457867
references.citation: Dev Cell. 2006 May;10(5):625-34
references.pmid: 16678777
references.citation: Nat Methods. 2012 Apr 01;9(5):477-9
references.pmid: 22466794
references.citation: Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11524-9
references.pmid: 21700882
references.citation: Curr Opin Struct Biol. 1996 Oct;6(5):663-70
references.pmid: 8913690
references.citation: Braz J Med Biol Res. 2006 Mar;39(3):313-20
references.pmid: 16501810
references.citation: JAMA. 1993 Dec 8;270(22):2713-6
references.pmid: 8133589
references.citation: Int Rev Cell Mol Biol. 2009;276:105-59
references.pmid: 19584012
references.citation: Development. 2002 Mar;129(5):1283-94
references.pmid: 11874923
references.citation: Annu Rev Biochem. 1999;68:729-77
references.pmid: 10872465
references.citation: J Biol Chem. 2003 Apr 4;278(14):11735-8
references.pmid: 12584198
references.citation: PLoS One. 2010 Nov 08;5(11):e15435
references.pmid: 21079745
references.citation: Dev Biol. 1996 Jan 10;173(1):228-42
references.pmid: 8575624
references.citation: Am J Hum Genet. 2013 May 2;92(5):725-43
references.pmid: 23643382
references.citation: Semin Cell Dev Biol. 2001 Apr;12(2):99-106
references.pmid: 11292375
references.citation: Curr Biol. 1999 Nov 18;9(22):1343-6
references.pmid: 10574766
references.citation: Dev Biol. 2006 Jun 15;294(2):352-65
references.pmid: 16677626
references.citation: Dev Neurobiol. 2011 Nov;71(11):901-23
references.pmid: 21714101
references.citation: J Cell Sci. 2004 Oct 1;117(Pt 21):5179-90
references.pmid: 15456854
references.citation: Curr Opin Neurobiol. 2006 Feb;16(1):40-51
references.pmid: 16417999
references.citation: Genetics. 1993 Oct;135(2):385-404
references.pmid: 8244003
references.citation: FEBS Lett. 1993 Jun 28;325(1-2):128-34
references.pmid: 8513884
references.citation: Sex Dev. 2008;2(4-5):181-93
references.pmid: 18987492
references.citation: Glycobiology. 2011 May;21(5):607-18
references.pmid: 21147759
references.citation: Proc Natl Acad Sci U S A. 2010 Aug 24;107(34):15140-4
references.pmid: 20696889
references.citation: G3 (Bethesda). 2013 Mar;3(3):541-52
references.pmid: 23451335
references.citation: Neuron. 2004 Mar 4;41(5):723-36
references.pmid: 15003172
references.citation: Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6346-51
references.pmid: 11983919
references.citation: Cell. 2013 Oct 10;155(2):296-307
references.pmid: 24120131
references.citation: Mol Cell Biol. 1997 Apr;17(4):2301-11
references.pmid: 9121480
references.citation: Development. 2001 Jun;128(11):1951-69
references.pmid: 11493519
references.citation: Cell. 2013 Oct 10;155(2):308-20
references.pmid: 24120132
references.citation: Development. 2005 Oct;132(20):4621-33
references.pmid: 16176946
references.citation: Science. 2013 Sep 20;341(6152):1404-8
references.pmid: 24052309
references.citation: PLoS Genet. 2006 Oct 20;2(10):e175
references.pmid: 17054399
references.citation: Philos Trans R Soc Lond B Biol Sci. 1986 Nov 12;314(1165):1-340
references.pmid: 22462104
references.citation: Genetics. 1974 May;77(1):71-94
references.pmid: 4366476
references.citation: Annu Rev Biochem. 2002;71:435-71
references.pmid: 12045103
references.citation: Endocr Rev. 1998 Oct;19(5):521-39
references.pmid: 9793755
references.citation: Nature. 2007 Apr 26;446(7139):1030-7
references.pmid: 17460664
references.citation: Dev Cell. 2002 Jan;2(1):115-24
references.pmid: 11782319
references.citation: Dev Biol. 2006 Nov 1;299(1):193-205
references.pmid: 16928366
references.citation: EMBO J. 2005 Apr 6;24(7):1477-88
references.pmid: 15775964
references.citation: Curr Biol. 2008 Dec 23;18(24):1978-85
references.pmid: 19062279
references.citation: Genes Dev. 1993 Aug;7(8):1471-84
references.pmid: 8393416
references.citation: Development. 1997 Sep;124(18):3565-73
references.pmid: 9342049
references.citation: Development. 2006 Sep;133(17):3329-40
references.pmid: 16887823
references.citation: J Cell Sci. 2009 Dec 15;122(Pt 24):4492-504
references.pmid: 19920077
references.citation: Annu Rev Cell Dev Biol. 2006;22:375-407
references.pmid: 16805665
references.citation: Nat Genet. 2001 Jun;28(2):160-4
references.pmid: 11381264