Mettl3 Mutation Disrupts Gamete Maturation and Reduces Fertility in Zebrafish

Abstract

N-methyladenosine (mA), catalyzed by Mettl3 methyltransferase, is a highly conserved epigenetic modification in eukaryotic messenger RNA (mRNA). Previous studies have implicated mA modification in multiple biological processes, but the function of mA has been difficult to study, because mutants are embryonic lethal in both mammals and plants. In this study, we have used transcription activator-like effector nucleases and generated viable zygotic mutant, Z , in zebrafish. We find that the oocytes in Z adult females are stalled in early development and the ratio of full-grown stage (FG) follicles is significantly lower than that of wild type. Human chorionic gonadotropin-induced ovarian germinal vesicle breakdown and the numbers of eggs ovulated are both decreased as well, while the defects of oocyte maturation can be rescued by sex hormone and In Z adult males, we find defects in sperm maturation and sperm motility is significantly reduced. Further study shows that 11-ketotestosterone (11-KT) and 17β-estradiol (E2) levels are significantly decreased in Z , and defective gamete maturation is accompanied by decreased overall mA modification levels and disrupted expression of genes critical for sex hormone synthesis and gonadotropin signaling in Z Thus, our study provides the first evidence that loss of Mettl3 leads to failed gamete maturation and significantly reduced fertility in zebrafish. Mettl3 and mA modifications are essential for optimal reproduction in vertebrates.

A dynamic reversible RNA N6‐methyladenosine modification: current status and perspectives

“…This study proves that METTL3 and m 6 A modifications are essential for reproduction in vertebrates (Xia et al, 2018). m 6 A methylation also regulates hematopoietic stem cells development.…”

The Effect of Huyang Yangkun Formula on N6-methyladenosine Modification in 4-vinylcyclohexene diepoxide Induced Premature Ovarian Insufficiency Rats

“…METTL3 was reported to promote the proliferation of ovarian granulosa cells, and another study also confirmed the promotion role in other cell lines; the mechanism may be that METTL3 helps facilitate DNA damage repair (Xiang et al, 2017). Also, knocking out METTL3 prevented the oocytes from maturing (Xia et al, 2018). METTL14 appears to play a supporting role of stabilizing METTL3 and helping to recognise RNA (Wang et al, 2017).…”

Role of m6A in Embryonic Stem Cell Differentiation and in Gametogenesis

“…METTL3 is widely expressed in different tissues in mouse and human, and when knocking-out METTL3 in mouse embryonic stem cells, no traces of m 6 A methylation can be found using mass spectrometry [31]. METTL3 was shown to play a major role in development and function of neural cells [40], cardiac cells [41,42], bone and muscle [43], hematopoiesis [44] and gametogenesis [45,46], as well as in cancer progression [47]. It was also shown in 2015 that it is essential for differentiation in vitro and for mouse development in vivo [31].…”

“…Loss of YTHDC1 leads to extensive polyadenylation and The first evidence for m 6 A importance during these processes in females was observed in zebrafish, showing that one-third of maternal mRNA is m 6 A-methylated, and its degradation, mediated by YTHDF2 activity, is important for maternal to zygotic transition and timely development of the zebrafish [109]. A later paper on zebrafish showed that loss of METTL3 results in failed gamete maturation and reduced fertility [45]. In mammals as well, YTHDF2 reader protein was the first link found between m 6 A and oogenesis: YTHDF2 is expressed throughout mouse oogenesis, as demonstrated by immunostaining [103].…”