maternal effect gene
NCBI Summary:
This gene encodes a putative peroxisomal protein that appears to be conserved across Euteleostomi. In humans, it may be autoantigenic. [provided by RefSeq, Jul 2010]
General function
RNA binding
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Cellular localization
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Ovarian function
Oocyte maturation
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Human MARF1 is an endoribonuclease that interacts with the DCP1:2 decapping complex and degrades target mRNAs. Nishimura T et al. (2018) Meiosis arrest female 1 (MARF1) is a cytoplasmic RNA binding protein that is essential for meiotic progression of mouse oocytes, in part by limiting retrotransposon expression. MARF1 is also expressed in somatic cells and tissues; however, its mechanism of action has yet to be investigated. Human MARF1 contains a NYN-like domain, two RRMs and eight LOTUS domains. Here we provide evidence that MARF1 post-transcriptionally silences targeted mRNAs. MARF1 physically interacts with the DCP1:DCP2 mRNA decapping complex but not with deadenylation machineries. Importantly, we provide a 1.7 Å resolution crystal structure of the human MARF1 NYN domain, which we demonstrate is a bona fide endoribonuclease, the activity of which is essential for the repression of MARF1-targeted mRNAs. Thus, MARF1 post-transcriptionally represses gene expression by serving as both an endoribonuclease and as a platform that recruits the DCP1:DCP2 decapping complex to targeted mRNAs.//////////////////
LOTUS domain protein MARF1 binds CCR4-NOT deadenylase complex to post-transcriptionally regulate gene expression in oocytes. Zhu L et al. (2018) Post-transcriptional regulation of gene expression plays an essential role during oocyte maturation. Here we report that Drosophila MARF1 (Meiosis Regulator And mRNA Stability Factor 1), which consists of one RNA-recognition motif and six tandem LOTUS domains with unknown molecular function, is essential for oocyte maturation. When tethered to a reporter mRNA, MARF1 post-transcriptionally silences reporter expression by shortening reporter mRNA poly-A tail length and thereby reducing reporter protein level. This activity is mediated by the MARF1 LOTUS domain, which binds the CCR4-NOT deadenylase complex. MARF1 binds cyclin A mRNA and shortens its poly-A tail to reduce Cyclin A protein level during oocyte maturation. This study identifies MARF1 as a regulator in oocyte maturation and defines the conserved LOTUS domain as a post-transcriptional effector domain that recruits CCR4-NOT deadenylase complex to shorten target mRNA poly-A tails and suppress their translation.//////////////////
Meiosis arrest female 1 (MARF1) has nuage-like function in mammalian oocytes. Su YQ et al. (2013) Orderly regulation of meiosis and protection of germline genomic integrity from transposable elements are essential for male and female gamete development. In the male germline, these processes are ensured by proteins associated with cytoplasmic nuage, but morphologically similar germ granules or nuage have not been identified in mammalian female germ cells. Indeed, many mutations affecting nuage-associated proteins such as PIWI and tudor domain containing proteins 5 and 7 (TDRD5/7) can result in failure of meiosis, up-regulation of retrotransposons, and infertility only in males and not in females. We recently identified MARF1 (meiosis arrest female 1) as a protein essential for controlling meiosis and retrotransposon surveillance in oocytes; and in contrast to PIWI-pathway mutations, Marf1 mutant females are infertile, whereas mutant males are fertile. Here we put forward the hypothesis that MARF1 in mouse oocytes is a functional counterpart of the nuage-associated components of spermatocytes. We describe the developmental pattern of Marf1 expression and its roles in retrotransposon silencing and protection from DNA double-strand breaks. Analysis of MARF1 protein domains compared with PIWI and TDRD5/7 revealed that these functional similarities are reflected in remarkable structural analogies. Thus, functions that in the male germline require protein interactions and cooperative scaffolding are combined in MARF1, allowing a single molecule to execute crucial activities of meiotic regulation and protection of germline genomic integrity.//////////////////
Interference with the C-terminal structure of MARF1 causes defective oocyte meiotic division and female infertility in mice. Cao GY et al. (2018) Meiosis-arrest female 1 (MARF1) is a recently identified key oogenic regulator essential for the maintenance of female fertility and genome integrity in mice. However, the detailed functions and the underlying mechanisms of MARF1 remain elusive. Here, in an attempt to create a mouse model expressing fluorescent protein-tagged MARF1 to facilitate further exploration of the roles of MARF1 in oocytes, we produced a Marf1-eGFP knockin (KI) mouse line in which the C-terminal structure and function of MARF1 were interfered by its fusing eGFP peptide. Using these Marf1-eGFP-KI mice, we revealed, unexpectedly, the functions of MARF1 in the control of oocyte meiotic division. We found that the Marf1-eGFP-KI females ovulated mature oocytes with severe meiotic and developmental defects, and thus were infertile. Moreover, meiotic reinitiation was delayed while meiotic completion was accelerated in the KI-oocytes, which was coincident with the increased incidence of oocyte aneuploidy. Therefore, MARF1 is indispensable for maintaining the fidelity of homolog segregation during oocyte maturation, and this function relies on its C-terminal domains.//////////////////
The RNA-binding protein MARF1 promotes cortical neurogenesis through its RNase activity domain. Kanemitsu Y et al. (2017) Cortical neurogenesis is a fundamental process of brain development that is spatiotemporally regulated by both intrinsic and extrinsic cues. Although recent evidence has highlighted the significance of transcription factors in cortical neurogenesis, little is known regarding the role of RNA-binding proteins (RBPs) in the post-transcriptional regulation of cortical neurogenesis. Here, we report that meiosis arrest female 1 (MARF1) is an RBP that is expressed during neuronal differentiation. Cortical neurons expressed the somatic form of MARF1 (sMARF1) but not the oocyte form (oMARF1). sMARF1 was enriched in embryonic brains, and its expression level decreased as brain development progressed. Overexpression of sMARF1 in E12.5 neuronal progenitor cells promoted neuronal differentiation, whereas sMARF1 knockdown decreased neuronal progenitor differentiation in vitro. We also examined the function of sMARF1 in vivo using an in utero electroporation technique. Overexpression of sMARF1 increased neuronal differentiation, whereas knockdown of sMARF1 inhibited differentiation in vivo. Moreover, using an RNase domain deletion mutant of sMARF1, we showed that the RNase domain is required for the effects of sMARF1 on cortical neurogenesis in vitro. Our results further elucidate the mechanisms of post-transcriptional regulation of cortical neurogenesis by RBPs.//////////////////
Expression regulated by
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Ovarian localization
Oocyte
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LMKB/MARF1 Localizes to mRNA Processing Bodies, Interacts with Ge-1, and Regulates IFI44L Gene Expression. Bloch DB 2014 et al.
The mRNA processing body (P-body) is a cellular structure that regulates the stability of cytoplasmic mRNA. MARF1 is a murine oocyte RNA-binding protein that is associated with maintenance of mRNA homeostasis and genomic stability. In this study, autoantibodies were used to identify Limkain B (LMKB), the human orthologue of MARF1, as a P-body component. Indirect immunofluorescence demonstrated that Ge-1 (a central component of the mammalian core-decapping complex) co-localized with LMKB in P-bodies. Two-hybrid and co-immunoprecipitation assays were used to demonstrate interaction between Ge-1 and LMKB. The C-terminal 120 amino acids of LMKB mediated interaction with Ge-1 and the N-terminal 1094 amino acids of Ge-1 were required for interaction with LMKB. LMKB is the first protein identified to date that interacts with this portion of Ge-1. LMKB was expressed in human B and T lymphocyte cell lines; depletion of LMKB increased expression of IFI44L, a gene that has been implicated in the cellular response to Type I interferons. The interaction between LMKB/MARF1, a protein that contains RNA-binding domains, and Ge-1, which interacts with core-decapping proteins, suggests that LMKB has a role in the regulation of mRNA stability. LMKB appears to have different functions in different cell types: maintenance of genomic stability in developing oocytes and possible dampening of the inflammatory response in B and T cells.
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Follicle stages
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Phenotypes
Mutations
2 mutations
Species: mouse
Mutation name: type: null mutation fertility: infertile - ovarian defect Comment: MARF1 regulates essential oogenic processes in mice. Su YQ et al. (2012) 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 messenger RNAs 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.//////////////////
Species: D. melanogaster
Mutation name: type: null mutation fertility: infertile - ovarian defect Comment: Drosophila MARF1 ensures proper oocyte maturation by regulating nanos expression. Kawaguchi S et al. (2020) Meiosis and oocyte maturation are tightly regulated processes. The meiosis arrest female 1 (MARF1) gene is essential for meiotic progression in animals; however, its detailed function remains unclear. In this study, we examined the molecular mechanism of dMarf1, a Drosophila homolog of MARF1 encoding an OST and RNA Recognition Motif (RRM) -containing protein for meiotic progression and oocyte maturation. Although oogenesis progressed in females carrying a dMarf1 loss-of-function allele, the dMarf1 mutant oocytes were found to contain arrested meiotic spindles or disrupted microtubule structures, indicating that the transition from meiosis I to II was compromised in these oocytes. The expression of the full-length dMarf1 transgene, but none of the variants lacking the OST and RRM motifs or the 47 conserved C-terminal residues among insect groups, rescued the meiotic defect in dMarf1 mutant oocytes. Our results indicate that these conserved residues are important for dMarf1 function. Immunoprecipitation of Myc-dMarf1 revealed that several mRNAs are bound to dMarf1. Of those, the protein expression of nanos (nos), but not its mRNA, was affected in the absence of dMarf1. In the control, the expression of Nos protein became downregulated during the late stages of oogenesis, while it remained high in dMarf1 mutant oocytes. We propose that dMarf1 translationally represses nos by binding to its mRNA. Furthermore, the downregulation of Nos induces cycB expression, which in turn activates the CycB/Cdk1 complex at the onset of oocyte maturation.//////////////////