MARF1 Regulates Essential Oogenic Processes in Mice

Abstract

Development of fertilization-competent oocytes depends on integrated processes controlling meiosis, cytoplasmic development, and maintenance of genomic integrity. We show that meiosis arrest female 1 (MARF1) is required for these processes in mammalian oocytes. Mutations of Marf1 cause female infertility characterized by up-regulation of a cohort of transcripts, increased retrotransposon expression, defective cytoplasmic maturation, and meiotic arrest. Up-regulation of protein phosphatase 2 catalytic subunit (PPP2CB) is key to the meiotic arrest phenotype. Moreover, Iap and Line1 retrotransposon mRNAs are also up-regulated, and, concomitantly, DNA double-strand breaks are elevated in mutant oocytes. Therefore MARF1, by suppressing levels of specific transcripts, is an essential regulator of important oogenic processes leading to female fertility and the development of healthy offspring.

PP2A regulates kinetochore-microtubule attachment during meiosis I in oocyte

“…18,19 In our study, the loss of PP2Acs did not significantly affect GVBD kinetics in oocytes under normal culture condition. It is worth determining whether DKO oocytes exhibit altered GVBD kinetics under challenging conditions.…”

“…Previous studies have shown that PP2A can inhibit GVBD in mouse oocytes. 18,19 We found that DKO oocytes showed indistinguishable GVBD kinetics compared to Ctrl oocytes when they were cultured in M2 medium (Fig. 1B).…”

“…17 Inactivation of PP2A by OA treatment or RNAi disturbs multiple events in oocyte meiosis, including GVBD, spindle assembly, chromosome segregation and cytokinesis. [18][19][20][21][22][23] How PP2A regulate female fertility, cannot be confirmed by in vitro research methods. Using genetically modified mouse model to study the in vivo roles of PP2A could provide more reliable evidence.…”

The methyltransferase Setdb1 is essential for meiosis and mitosis in mouse oocytes and early embryos

“…Setdb1-mediated H3K9me3 and DNA methylation have been implicated in the silencing of LTR elements in undifferentiated and differentiated cells, respectively (Hutnick et al, 2010;Matsui et al, 2010;Walsh et al, 1998). Setdb1 controls H3K9me3 deposition at and silencing of several class I ERV1 and class II ERVK retrotransposons in ESCs, PGCs and in Milrinone and Rp-cAMP are inhibitors of PDE3A and PKA, respectively (modified from Su et al, 2012). (C) Percentage of GVBD at 2 h and 18 h after milrinone removal for oocytes treated with or without Rp-cAMP.…”

The LOTUS domain is a conserved DEAD-box RNA helicase regulator essential for the recruitment of Vasa to the germ plasm and nuage

“…Like Oskar, the proteins TDRD5, TDRD7, and MARF1 play critical roles in germ cell development in animals, but their molecular function is not known. In mice, MARF1 is oocyte-specific and required for meiotic progression, and MARF1 mutant mouse females are sterile (Su et al 2012). In contrast, mammalian TDRD5 and TDRD7 have important roles during spermatogenesis, and TDRD5-or TDRD7-deficient males are sterile (Lachke et al 2011;Tanaka et al 2011;Yabuta et al 2011).…”