title: An NAD(+) biosynthetic pathway enzyme functions cell non-autonomously in C. elegans development.
abstract: BACKGROUND
  Disruption of cellular metabolite levels can adversely impact development. Specifically, loss-of-function of the C. elegans NAD(+) salvage biosynthesis gene PNC-1 results in an array of developmental phenotypes. Intriguingly, PNC-1 and its functional equivalent in vertebrates are secreted, but the contributions of the extracellular enzymes are poorly understood. We sought to study the tissue-specific requirements for PNC-1 expression and to examine the role of the secreted isoform.
  
  
  RESULTS
  A thorough analysis of PNC-1 expression did not detect expression in tissues that require PNC-1 function. Limited expression of both the secreted and intracellular PNC-1 isoforms provided function at a distance from the tissues with phenotypes. We also find that the secreted isoform contributes to in vivo PNC-1 activity. Furthermore, uv1 cell survival has the most stringent requirements in terms of PNC-1 expression pattern or level.
  
  
  CONCLUSIONS
  Using careful promoter analysis and a restricted expression approach, we have shown that both the secreted and the intracellular PNC-1 isoforms function cell non-autonomously, and that the PNC-1a isoform is functionally relevant in vivo. Our work suggests a model where PNC-1 function is provided cell non-autonomously by a mix of intra and extracellular activity, most likely requiring NAD(+) salvage metabolite transport between tissues.
authors.affiliation: Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania.
authors.forename: Matt
authors.initials: M
authors.lastname: Crook
authors.forename: Melanie R
authors.initials: MR
authors.lastname: Mcreynolds
authors.forename: Wenqing
authors.initials: W
authors.lastname: Wang
authors.forename: Wendy
authors.initials: W
authors.lastname: Hanna-Rose
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000201:enzymology* / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D020033:Protein Isoforms
keywords: NAD+ salvage biosynthesis; Nampt; Pnc1; nicotinamide; nicotinic acid; vitamin B3
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