title: C. elegans pharyngeal morphogenesis requires both de novo synthesis of pyrimidines and synthesis of heparan sulfate proteoglycans.
abstract: The C. elegans pharynx undergoes elongation and morphogenesis to its characteristic bi-lobed shape between the 2- and 3-fold stages of embryogenesis. During this period, the pharyngeal muscles and marginal cells forming the isthmus between the anterior and posterior pharyngeal bulbs elongate and narrow. We have identified the spontaneous mutant pyr-1(cu8) exhibiting defective pharyngeal isthmus elongation, cytoskeletal organization defects, and maternal effect lethality. pyr-1 encodes CAD, a trifunctional enzyme required for de novo pyrimidine synthesis, and pyr-1(cu8) mutants are rescued by supplying exogenous pyrimidines. Similar pharyngeal defects and maternal effect lethality were found in sqv-1, sqv-8, rib-1 and rib-2 mutants, which affect enzymes involved in heparan sulfate proteoglycan (HSPG) synthesis. rib-1 mutant lethality was enhanced in a pyr-1 mutant background, indicating that HSPG synthesis is very sensitive to decreased pyrimidine pools, and HS disaccharides are moderately decreased in both rib-1 and pyr-1 mutants. We hypothesize that HSPGs are necessary for pharyngeal isthmus elongation, and pyr-1 functions upstream of proteoglycan synthesizing enzymes by providing precursors of UDP-sugars essential for HSPG synthesis.
authors.affiliation: Department of Biological Sciences and the Laboratory for Molecular Biology, University of Illinois at Chicago, 900 S. Ashland Avenue, Chicago, IL 60607, USA.
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Franks
authors.forename: Tomomi
authors.initials: T
authors.lastname: Izumikawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kitagawa
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Sugahara
authors.forename: Peter G
authors.initials: PG
authors.lastname: Okkema
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001221:Aspartate Carbamoyltransferase / Q000235:genetics* / Q000502:physiology; D017173:Caenorhabditis elegans / Q000196:embryology* / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000502:physiology; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing) / Q000235:genetics* / Q000502:physiology; D004080:Dihydroorotase / Q000235:genetics* / Q000502:physiology; D015801:Helminth Proteins / Q000235:genetics* / Q000502:physiology; D019812:Heparan Sulfate Proteoglycans / Q000096:biosynthesis* / Q000235:genetics; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000235:genetics / Q000502:physiology; D009154:Mutation; D010614:Pharynx / Q000196:embryology* / Q000378:metabolism; D011743:Pyrimidines / Q000096:biosynthesis*
chemical_list: C033626:CAD trifunctional enzyme; D029742:Caenorhabditis elegans Proteins; D015801:Helminth Proteins; D019812:Heparan Sulfate Proteoglycans; D009097:Multienzyme Complexes; D011743:Pyrimidines; D001221:Aspartate Carbamoyltransferase; D004080:Dihydroorotase; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)