Primordial germ cells (PGCs) form during early embryogenesis with a supply of maternal mRNAs that contain shorter poly(A) tails. How translation of maternal mRNAs is regulated during PGC development remains elusive. Here we describe a small-molecule screen with zebrafish embryos that identified primordazine, a compound that selectively ablates PGCs. Primordazine’s effect on PGCs arises from translation repression through primordazine-response elements in the 3′ UTRs. Systematic dissection of primordazine’s mechanism of action revealed that translation of mRNAs during early embryogenesis occurs by two distinct pathways, depending on the length of their poly(A) tails. In addition to poly(A)-tail-dependent translation (PAT), early embryos perform poly(A)-tail-independent noncanonical translation (PAINT) via deadenylated 3′ UTRs. Primordazine inhibits PAINT without inhibiting PAT, an effect that was also observed in quiescent, but not proliferating, mammalian cells. These studies reveal that PAINT is an alternative form of translation in the early embryo and is indispensable for PGC maintenance.
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Retention of paternal DNA methylome in the developing zebrafish germline
Nature Communications Open Access 11 July 2019
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The data that support the findings of this study including RNA-seq and proteomics analysis are available from the corresponding authors upon reasonable request.
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We thank S. Vasudevan, T. Shioda, S. Lee, N. Dyson, W. Miles, and Y. Yu for discussions related to this manuscript. Thanks to K. Inoue (Kobe University, Japan), E. Raz (University of Münster, Germany), M. Bushell (MedicalResearch Council, UK), and J. Wilusz (University of Pennsylvania, USA) for providing plasmids. Thanks to U. Kim (next generation sequencing core at Massachusetts General Hospital) for help with the RNA-seq process, to A. Gonzales and D. Harrison for technical assistance, and to C. Reilly for chemical validation. Funding was provided by NIH grants 5T32HL007208-37 (Y.N.J.), R01GM088040 (R.T.P.), USDA grant 2014-07998 (R.T.P.), the Charles and Ann Sanders MGH Scholar Award (R.T.P.), and the L. S. Skaggs Presidential Endowed Chair (R.T.P.).
P.J.S. and R.T.P. have applied for a patent for primordazine.
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Jin, Y.N., Schlueter, P.J., Jurisch-Yaksi, N. et al. Noncanonical translation via deadenylated 3′ UTRs maintains primordial germ cells. Nat Chem Biol 14, 844–852 (2018). https://doi.org/10.1038/s41589-018-0098-0
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