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Published August 2005 | public
Journal Article

Analysis of the Zebrafish perplexed Mutation Reveals Tissue-Specific Roles for de Novo Pyrimidine Synthesis During Development

Abstract

The zebrafish perplexed mutation disrupts cell proliferation and differentiation during retinal development. In addition, growth and morphogenesis of the tectum, jaw, and pectoral fins are also affected. Positional cloning was used to identify a mutation in the carbamoyl-phosphate synthetase2-aspartate transcarbamylase-dihydroorotase (cad) gene as possibly causative of the perplexed mutation and this was confirmed by gene knockdown and pyrimidine rescue experiments. CAD is required for de novo biosynthesis of pyrimidines that are required for DNA, RNA, and UDP-dependent protein glycosylation. Developmental studies of several vertebrate species showed high levels of cad expression in tissues where mutant phenotypes were observed. Confocal time-lapse analysis of perplexed retinal cells in vivo showed a near doubling of the cell cycle period length. We also compared the perplexed mutation with mutations that affect either DNA synthesis or UDP-dependent protein glycosylation. Cumulatively, our results suggest an essential role for CAD in facilitating proliferation and differentiation events in a tissue-specific manner during vertebrate development. Both de novo DNA synthesis and UDP-dependent protein glycosylation are important for the perplexed phenotypes.

Additional Information

© 2005 by the Genetics Society of America. Manuscript received February 6, 2005. Accepted for publication April 25, 2005. We thank Adam Amsterdam and Jeff Gross for sharing data and mutant lines prior to publication. We also gratefully acknowledge the technical assistance from Michael Cliff and Melissa Reske. This project was funded by American Heart Association grant 0225071Y (V.L.), National Institutes of Health grant RO1EY01467 (B.L.), and a March of Dimes Basil O'Connor Fellowship (B.L.).

Additional details

Created:
August 19, 2023
Modified:
October 20, 2023