Kyle Begovich1,2, Deborah Yelon2, James E Wilhelm1,2. 1. Howard Hughes Medical Institute (HHMI) Summer Institute, Marine Biological Laboratory, Woods Hole, Massachusetts, USA. 2. Division of Biological Sciences, University of California, San Diego, California, USA.
Abstract
BACKGROUND: The self-assembly of metabolic enzymes into filaments or foci highlights an intriguing mechanism for the regulation of metabolic activity. Recently, we identified the conserved polymerization of phosphoribosyl pyrophosphate synthetase (PRPS), which catalyzes the first step in purine nucleotide synthesis, in yeast and cultured mammalian cells. While previous work has revealed that loss of PRPS activity regulates retinal development in zebrafish, the extent to which PRPS filament formation affects tissue development remains unknown. RESULTS: By generating novel alleles in the zebrafish PRPS paralogs, prps1a and prps1b, we gained new insight into the role of PRPS filaments during eye development. We found that mutations in prps1a alone are sufficient to generate abnormally small eyes along with defects in head size, pigmentation, and swim bladder inflation. Furthermore, a loss-of-function mutation that truncates the Prps1a protein resulted in the failure of PRPS filament assembly. Lastly, in mutants that fail to assemble PRPS filaments, we observed disorganization of the actin network in the lens fibers. CONCLUSIONS: The truncation of Prps1a blocked PRPS filament formation and resulted in a disorganized lens fiber actin network. Altogether, these findings highlight a potential role for PRPS filaments during lens fiber organization in zebrafish.
BACKGROUND: The self-assembly of metabolic enzymes into filaments or foci highlights an intriguing mechanism for the regulation of metabolic activity. Recently, we identified the conserved polymerization of phosphoribosyl pyrophosphate synthetase (PRPS), which catalyzes the first step in purine nucleotide synthesis, in yeast and cultured mammalian cells. While previous work has revealed that loss of PRPS activity regulates retinal development in zebrafish, the extent to which PRPS filament formation affects tissue development remains unknown. RESULTS: By generating novel alleles in the zebrafish PRPS paralogs, prps1a and prps1b, we gained new insight into the role of PRPS filaments during eye development. We found that mutations in prps1a alone are sufficient to generate abnormally small eyes along with defects in head size, pigmentation, and swim bladder inflation. Furthermore, a loss-of-function mutation that truncates the Prps1a protein resulted in the failure of PRPS filament assembly. Lastly, in mutants that fail to assemble PRPS filaments, we observed disorganization of the actin network in the lens fibers. CONCLUSIONS: The truncation of Prps1a blocked PRPS filament formation and resulted in a disorganized lens fiber actin network. Altogether, these findings highlight a potential role for PRPS filaments during lens fiber organization in zebrafish.
Authors: Rammohan Narayanaswamy; Matthew Levy; Mark Tsechansky; Gwendolyn M Stovall; Jeremy D O'Connell; Jennifer Mirrielees; Andrew D Ellington; Edward M Marcotte Journal: Proc Natl Acad Sci U S A Date: 2009-06-05 Impact factor: 11.205
Authors: Alessia Fiorentino; Kaoru Fujinami; Gavin Arno; Anthony G Robson; Nikolas Pontikos; Monica Arasanz Armengol; Vincent Plagnol; Takaaki Hayashi; Takeshi Iwata; Matthew Parker; Tom Fowler; Augusto Rendon; Jessica C Gardner; Robert H Henderson; Michael E Cheetham; Andrew R Webster; Michel Michaelides; Alison J Hardcastle Journal: Hum Mutat Date: 2017-10-17 Impact factor: 4.878
Authors: Chalongrat Noree; Kyle Begovich; Dane Samilo; Risa Broyer; Elena Monfort; James E Wilhelm Journal: Mol Biol Cell Date: 2019-09-04 Impact factor: 4.138