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.
BACKGROUND: Disruption of cellular metabolite levels can adversely impact development. Specifically, loss-of-function of the C. elegansNAD(+) 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: Julia Skokowa; Dan Lan; Basant Kumar Thakur; Fei Wang; Kshama Gupta; Gunnar Cario; Annette Müller Brechlin; Axel Schambach; Lars Hinrichsen; Gustav Meyer; Matthias Gaestel; Martin Stanulla; Qiang Tong; Karl Welte Journal: Nat Med Date: 2009-02-01 Impact factor: 53.440
Authors: Olga M Ocón-Grove; Susan M Krzysik-Walker; Sreenivasa R Maddineni; Gilbert L Hendricks; Ramesh Ramachandran Journal: Reproduction Date: 2010-01 Impact factor: 3.906
Authors: Adem Ozcelik; Nitesh Nama; Po-Hsun Huang; Murat Kaynak; Melanie R McReynolds; Wendy Hanna-Rose; Tony Jun Huang Journal: Small Date: 2016-08-12 Impact factor: 13.281