RRC ID 45724
Author Díaz-Balzac CA, Lázaro-Peña MI, Tecle E, Gomez N, Bülow HE.
Title Complex cooperative functions of heparan sulfate proteoglycans shape nervous system development in Caenorhabditis elegans.
Journal G3 (Bethesda)
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.
Volume 4(10)
Pages 1859-70
Published 2014-8-5
DOI 10.1534/g3.114.012591
PII g3.114.012591
PMID 25098771
PMC PMC4199693
MeSH Alleles Animals Caenorhabditis elegans / growth & development* Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism Glypicans / metabolism Heparan Sulfate Proteoglycans / chemistry Heparan Sulfate Proteoglycans / metabolism* Interneurons / metabolism Kallmann Syndrome / pathology Kallmann Syndrome / veterinary Membrane Proteins / metabolism Mutagenesis Nerve Tissue Proteins / genetics Nerve Tissue Proteins / metabolism Nervous System / metabolism* Pentosyltransferases / genetics Pentosyltransferases / metabolism Proteoglycans / metabolism Sulfotransferases / genetics Sulfotransferases / metabolism UDP Xylose-Protein Xylosyltransferase
IF 2.781
Times Cited 15
WOS Category GENETICS & HEREDITY
Resource
C.elegans tm472 tm3006