Heng-Yu Fan’s Group Reported the Function of ZAR1 and ZAR2 in Regulating the Maternal Transcriptome and mRNA Translational Activation in Nucleic Acids Research

编辑: Date:2019/10/14

On October 10th, 2019, prof. Heng-Yu Fan’s group published a paper entitled “ZAR1 and ZAR2 are required for oocyte meiotic maturation by regulating the maternal transcriptome and mRNA translational activation” in Nucleic Acids Research (Impact factor 11.14), which reported the key function of two maternal factors, ZAR1 and ZAR2, in oocyte meiosis.

Different from other cells, oocytes became larger quickly during the follicular development, along with active transcription. Numerous mRNAs stored to support oocyte maturation and early embryogenesis were not immediately translated after synthesis. After meiosis resumption, they would be translated group by group into proteins actively. Thus, the mechanisms of mRNA stability maintenance and translational regulation were badly in need to be clarified. They were vital for oocyte meiosis, embryonic development and assistant reproductive technology.

The gene, whose gene products stored in the ooplasm did not affected oocyte meiosis but affected early embryonic development, was called Maternal-effect gene”. Zygote arrest-1 (ZAR1), identified in mammals this century, was considered one of the earliest identified maternal effect factors. Female mice null for Zar1 were infertile since embryogenesis was blocked at the 1-cell stage. This important study established Zar1 as one of the best known mammalian maternal-effect genes that functioned during the maternal-zygotic transition (MZT). However, the function of Zar1 in oocytes and its precise molecular mechanism still remained unknown in the past 20 years. Besides, a Zar1-like (Zar1l, or Zar2) gene shared high homology with Zar1, particularly the sequences encoding the C-terminal RNA-binding domain, and was also conserved throughout the vertebrate lineage. Although it was reported that overexpression of ZAR2 C-terminus in mouse zygotes induced 2-cell stage arrest, the physiological function of ZAR2 had not yet been investigated in vivo.

Fans group knocked out Zar1 and Zar2 in the mouse genome and proved their potential redundant function. While Zar2 knockout alone caused no visible phenotypes, it strengthened Zar1 knockout phenotypes. The double deletion of Zar1 and Zar2 (Zar1/2) impaired oocyte meiotic cell cycle progression (Fig. 1). Therefore, this study revealed previously unrecognized functions of ZAR1/2 in oocyte maturation and suggested that the failure of MZT observed in maternal Zar1-deleted zygotes was a consequence of defective meiotic maturation.

 

Fig. 1: In vitro maturation of oocytes showed that Zar1/2 deleted oocytes could not extrude the first polar body (PB1) or develop into mature eggs.

 

They found that Zar1/2 knockout did not affect transcription but reduced mRNAs in oocytes and impaired translational activation of maternal mRNAs encoding important meiosis and MZT factors. For example, the cell-cycle proteins cyclin B1 and WEE2, spindle assembly protein TPX2 and MZT licensing factor BTG4 could not be translated in ovulated Zar1/2 deleted oocytes because of the failure of polyadenylation. Besides mRNA, ZAR1/2 could interact with other oocyte proteins directly, such as mRNA-stabilizing protein MSY2 and cytoplasmic lattice components, to maintain mRNA stability (Fig. 2). Thus, ZAR1/2 are required for oocyte meiotic maturation and MZT by regulating the maternal transcriptome and mRNA translational activation.

 

Fig. 2: ZAR1/2 regulate the maternal transcriptome and mRNA translational activation.

 

This study proved that ZAR1/2 functioned in maintaining mRNA stability and translational activation to ensure oocyte meiosis and early embryonic development. Graduate student Yan Rong and Dr. Shu-Yan Ji are co-first authors of this study. Prof. Fan and Dr. Shu-Yan Ji are the co-corresponding authors.

 

Links: https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkz863/5584529