The nucleolar protein NOP2 is required for nucleolar maturation and ribosome biogenesis during preimplantation development in mammals

Abstract

The maternal nucleolus plays an indispensable role in zygotic genome activation (ZGA) and early embryonic development in mice. During oocyte-to-embryo transition, the nucleolus is subject to substantial transformation. Despite the primary role of the nucleolus is ribosome biogenesis, accumulating evidence has uncovered its functions in various other cell processes. However, the regulation of nucleolar maturation and ribosome biogenesis and the molecules involved remain unclear during early embryonic development. In this study, we observed that nucleolar protein 2 (NOP2) is restrictedly localized within the nucleolus, first detected in the late two-cell embryos, and increases to a peak level at the eight-cell stage in mice. RNAi-mediated NOP2 depletion leads to a developmental arrest during the morula-to-blastocyst transition. RNA-seq analyses reveal that 208 genes are differentially expressed, including multiple lineage-specific genes and several genes encoding ribosome proteins.Indeed, we observe a failure of the first lineage specification with reduced TEA domain transcription factor 4(TEAD4) (trophectoderm-specific), tir na nog (NANOG), and kruppel-like factor 4 (KLF4) (inner cell mass-specific). Importantly, by Transm ission Electron Microscopy (TEM), we noted a decrease in the ratio of the nucleolus size and an increase in the ratio of the size of the nucleolus precursor body, suggesting the nucleolar maturation is disrupted. Moreover, both qPCR and Fluorescence I n Situ Hybridization (FISH) data showcase a significant decrease in the abundance of ribosome RNAs. Similarly, NOP2 depletion causes reduced developmental potential and decreased rRNA level in bovine early embryos, suggesting a functional 2716 |

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“…The assembly of 40S and 60S ribosomal subunits is regulated by DEAD-box RNA helicase 18 (DDX18) [ 26 ]. Nucleolar protein 2 (NOP2/NSUN1), which can inhibit HIV-1 transcription and promote viral latency [ 27 ], is also required for nucleolar maturation and ribosome biogenesis in mammals [ 28 ]. Ribosomal protein L4 (RPL4) is known to affect tumorigenesis and metastasis of HCC [ 29 ] and to participate in the assembly of pre-60S in the nucleus [ 30 ].…”

Genetic causes of preimplantation embryo developmental failure

“…They showed that NOP2 depletion causes: developmental arrest during the morula‐to‐blastocyst transition in mouse and bovine models; disruption of the first lineage specification program with reduced level of key lineage‐specific genes, including TEAD4, NANOG, and KLF4; disruption of nucleolar size and composition, as well as, reduced levels of rRNAs and several genes encoding ribosome proteins. In conclusion, NOP2 was found to be essential during preimplantation development in mammals, playing a critical role in nucleolar maturation and ribosome biogenesis (H. Wang et al, 2020). In addition to NOP2, another nucleolar protein, NOC4L, was previously associated with embryonic lethality during the preimplantation stages of development.…”

Variations in transfer and ribosomal RNA epitranscriptomic status can adapt eukaryote translation to changing physiological and environmental conditions

“…Another conserved methyltransferase, NOP2(NSUN1), is involved in converting a second large subunit rRNA cytidine (in position 2870 for yeast, 2982 for nematodes and 4417 for human) in m 5 C. In yeast and human, NOP2(NSUN1) is essential for rRNA processing and synthesis of the large ribosome subunit, a function that is independent of its m 5 C modification activity [161][162][163]. Accordingly, NOP2 (NSUN1) is essential for yeast growth and mammalian embryo development [161,162]. This is not the case for nematodes, as nsun1 worms are viable and not significantly affected in ribosome biogenesis nor in global translation [164] (a situation analogous to what is observed in nsun5 worms [149]).…”