scholarly journals Positive mRNA Translational Control in Germ Cells by Initiation Factor Selectivity

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Andrew J. Friday ◽  
Brett D. Keiper
Keyword(s):  
Germ Cell ◽  
Germ Cells ◽  
Translation Initiation ◽  
Translational Control ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Positive Function ◽  
Initiation Factor ◽  
C Elegans ◽  
Initiation Factors

Ultimately, the production of new proteins in undetermined cells pushes them to new fates. Other proteins hold a stem cell in a mode of self-renewal. In germ cells, these decision-making proteins are produced largely from translational control of preexisting mRNAs. To date, all of the regulation has been attributed to RNA binding proteins (RBPs) that repress mRNAs in many models of germ cell development (Drosophila, mouse,C. elegans, andXenopus). In this review, we focus on the selective, positive function of translation initiation factors eIF4E and eIF4G, which recruit mRNAs to ribosomes upon derepression. Evidence now shows that the two events are not separate but rather are coordinated through composite complexes of repressors and germ cell isoforms of eIF4 factors. Strikingly, the initiation factor isoforms are themselves mRNA selective. The mRNP complexes of translation factors and RBPs are built on specific populations of mRNAs to prime them for subsequent translation initiation. Simple rearrangement of the partners causes a dormant mRNP to become synthetically active in germ cells when and where they are required to support gametogenesis.

scholarly journals Multi-modal regulation of C. elegans hermaphrodite spermatogenesis by the GLD-1-FOG-2 complex

2018 ◽  
Author(s):  
Shuang Hu ◽  
Lauren E. Ryan ◽  
Ebru Kaymak ◽  
Lindsay Freeberg ◽  
Te-Wen Lo ◽  
...  
Keyword(s):  
Sex Determination ◽  
Germ Cell ◽  
Germ Cells ◽  
Translational Control ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Wild Type ◽  
C Elegans ◽  
Target Mrnas ◽  
Mrna Targets

AbstractProper germ cell sex determination in Caenorhabditis nematodes requires a network of RNA-binding proteins (RBPs) and their target mRNAs. In some species, changes in this network enabled limited XX spermatogenesis, and thus self-fertility. In C. elegans, one of these selfing species, the global sex-determining gene tra-2 is regulated in germ cells by a conserved RBP, GLD-1, via the 3’ untranslated region (3’UTR) of its transcript. A C. elegans-specific GLD-1 cofactor, FOG-2, is also required for hermaphrodite sperm fate, but how it modifies GLD-1 function is unknown. Germline feminization in gld-1 and fog-2 null mutants has been interpreted as due to cell-autonomous elevation of TRA-2 translation. Consistent with the proposed role of FOG-2 in translational control, the abundance of nearly all GLD-1 target mRNAs (including tra-2) is unchanged in fog-2 mutants. Epitope tagging reveals abundant TRA-2 expression in somatic tissues, but an undetectably low level in wild-type germ cells. Loss of gld-1 function elevates germline TRA-2 expression to detectable levels, but loss of fog-2 function does not. A simple quantitative model of tra-2 activity constrained by these results can successfully sort genotypes into normal or feminized groups. Surprisingly, fog-2 and gld-1 activity enable the sperm fate even when GLD-1 cannot bind to the tra-2 3’ UTR. This suggests the GLD-1-FOG-2 complex regulates uncharacterized sites within tra-2, or other mRNA targets. Finally, we quantify the RNA-binding capacities of dominant missense alleles of GLD-1 that act genetically as “hyperrepressors” of tra-2 activity. These variants bind RNA more weakly in vitro than does wild-type GLD-1. These results indicate that gld-1 and fog-2 regulate germline sex via multiple interactions, and that our understanding of the control and evolution of germ cell sex determination in the C. elegans hermaphrodite is far from complete.

scholarly journals Functional reconstruction of NANOS3 expression in the germ cell lineage by a novel transgenic reporter reveals distinct subcellular localizations of NANOS3

Reproduction ◽  
2010 ◽  
Vol 139 (2) ◽  
pp. 381-393 ◽  
Author(s):  
Masashi Yamaji ◽  
Takashi Tanaka ◽  
Mayo Shigeta ◽  
Shinichiro Chuma ◽  
Yumiko Saga ◽  
...  
Keyword(s):  
Germ Cell ◽  
Germ Cells ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Primordial Germ Cells ◽  
Cell Lineage ◽  
Regulatory Elements ◽  
Initiation Factor ◽  
Processing Bodies

Mutations of RNA-binding proteins such as NANOS3, TIAL1, and DND1 in mice have been known to result in the failure of survival and/or proliferation of primordial germ cells (PGCs) soon after their fate is specified (around embryonic day (E) 8.0), leading to the infertility of these animals. However, the mechanisms of actions of these RNA-binding proteins remain largely unresolved. As a foundation to explore the role of these RNA-binding proteins in germ cells, we established a novel transgenic reporter strain that expresses NANOS3 fused with EGFP under the control of Nanos3 regulatory elements. NANOS3–EGFP exhibited exclusive expression in PGCs as early as E7.25, and continued to be expressed in female germ cells until around E14.5 and in male germ cells throughout the fetal period with declining expression levels after E16.5. NANOS3–EGFP resumed strong expression in postnatal spermatogonia and continued to be expressed in undifferentiated spermatogonial cells in adults. Importantly, the Nanos3–EGFP transgene rescued the sterile phenotype of Nanos3 homozygous mutants, demonstrating the functional equivalency of NANOS3–EGFP with endogenous NANOS3. We found that throughout germ cell development, a predominant amount of  NANOS3–EGFP co-localized with TIAL1 (also known as TIAR) and phosphorylated eukaryotic initiation factor 2α, markers for the stress granules, whereas a fraction of it showed co-localization with DCP1A, a marker for the processing bodies. On the other hand, NANOS3–EGFP did not co-localize with Tudor domain-containing protein 1, a marker for the intermitochondrial cements, in spermatogenic cells. These findings unveil the presence of distinct posttranscriptional regulations in PGCs soon after their specification, for which RNA-binding proteins such as NANOS3 and TIAL1 would play critical functions.

scholarly journals Cap-Independent mRNA Translation in Germ Cells

2019 ◽  
Vol 20 (1) ◽  
pp. 173 ◽  
Author(s):  
Brett D. Keiper
Keyword(s):  
Germ Cell ◽  
Germ Cells ◽  
Translation Initiation ◽  
Translational Control ◽  
Structural Damage ◽  
Mrna Translation ◽  
Initiation Factor ◽  
Cellular Mrnas ◽  
A Minor ◽  
Oocyte Differentiation

Cellular mRNAs in plants and animals have a 5′-cap structure that is accepted as the recognition point to initiate translation by ribosomes. Consequently, it was long assumed that the translation initiation apparatus was built solely for a cap-dependent (CD) mechanism. Exceptions that emerged invoke structural damage (proteolytic cleavage) to eukaryotic initiation factor 4 (eIF4) factors that disable cap recognition. The residual eIF4 complex is thought to be crippled, but capable of cap-independent (CI) translation to recruit viral or death-associated mRNAs begrudgingly when cells are in great distress. However, situations where CI translation coexists with CD translation are now known. In such cases, CI translation is still a minor mechanism in the major background of CD synthesis. In this review, I propose that germ cells do not fit this mold. Using observations from various animal models of oogenesis and spermatogenesis, I suggest that CI translation is a robust partner to CD translation to carry out the translational control that is so prevalent in germ cell development. Evidence suggests that CI translation provides surveillance of germ cell homeostasis, while CD translation governs the regulated protein synthesis that ushers these meiotic cells through the remarkable steps in sperm/oocyte differentiation.

scholarly journals The DAZL and PABP families: RNA-binding proteins with interrelated roles in translational control in oocytes

Reproduction ◽  
2009 ◽  
Vol 137 (4) ◽  
pp. 595-617 ◽  
Author(s):  
Matthew Brook ◽  
Joel W S Smith ◽  
Nicola K Gray
Keyword(s):  
Gene Expression ◽  
Germ Cells ◽  
Translational Control ◽  
Translational Regulation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Regulation Of Gene Expression ◽  
Mrna Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor

Gametogenesis is a highly complex process that requires the exquisite temporal, spatial and amplitudinal regulation of gene expression at multiple levels. Translational regulation is important in a wide variety of cell types but may be even more prevalent in germ cells, where periods of transcriptional quiescence necessitate the use of post-transcriptional mechanisms to effect changes in gene expression. Consistent with this, studies in multiple animal models have revealed an essential role for mRNA translation in the establishment and maintenance of reproductive competence. While studies in humans are less advanced, emerging evidence suggests that translational regulation plays a similarly important role in human germ cells and fertility. This review highlights specific mechanisms of translational regulation that play critical roles in oogenesis by activating subsets of mRNAs. These mRNAs are activated in a strictly determined temporal manner via elements located within their 3′UTR, which serve as binding sites fortrans-acting factors. While we concentrate on oogenesis, these regulatory events also play important roles during spermatogenesis. In particular, we focus on the deleted in azoospermia-like (DAZL) family of proteins, recently implicated in the translational control of specific mRNAs in germ cells; their relationship with the general translation initiation factor poly(A)-binding protein (PABP) and the process of cytoplasmic mRNA polyadenylation.

nos-1 and nos-2, two genes related to Drosophila nanos, regulate primordial germ cell development and survival in Caenorhabditis elegans

Development ◽  
1999 ◽  
Vol 126 (21) ◽  
pp. 4861-4871 ◽  
Author(s):  
K. Subramaniam ◽  
G. Seydoux
Keyword(s):  
Caenorhabditis Elegans ◽  
Germ Cell ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Primordial Germ Cell ◽  
Gene Families ◽  
Cell Development ◽  
Embryonic Patterning ◽  
Germ Cell Development ◽  
C Elegans

In Drosophila, the posterior determinant nanos is required for embryonic patterning and for primordial germ cell (PGC) development. We have identified three genes in Caenorhabditis elegans that contain a putative zinc-binding domain similar to the one found in nanos, and show that two of these genes function during PGC development. Like Drosophila nanos, C. elegans nos-1 and nos-2 are not generally required for PGC fate specification, but instead regulate specific aspects of PGC development. nos-2 is expressed in PGCs around the time of gastrulation from a maternal RNA associated with P granules, and is required for the efficient incorporation of PGCs into the somatic gonad. nos-1 is expressed in PGCs after gastrulation, and is required redundantly with nos-2 to prevent PGCs from dividing in starved animals and to maintain germ cell viability during larval development. In the absence of nos-1 and nos-2, germ cells cease proliferation at the end of the second larval stage, and die in a manner that is partially dependent on the apoptosis gene ced-4. Our results also indicate that putative RNA-binding proteins related to Drosophila Pumilio are required for the same PGC processes as nos-1 and nos-2. These studies demonstrate that evolutionarily distant organisms utilize conserved factors to regulate early germ cell development and survival, and that these factors include members of the nanos and pumilio gene families.

scholarly journals Translational specialization in pluripotency by RBPMS poises future lineage-decisions

2021 ◽  
Author(s):  
Deniz Bartsch ◽  
Kaustubh Kalamkar ◽  
Gaurav Ahuja ◽  
Hisham Bazzi ◽  
Argyris Papantonis ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Fate ◽  
Translation Initiation ◽  
Translational Control ◽  
Rna Binding ◽  
Rna Binding Protein ◽  
Lineage Commitment ◽  
Initiation Factors ◽  
Translation Initiation Factors ◽  
Selective Translation

SUMMARYIn mammals, translation is uniquely regulated at the exit of pluripotency to rapidly reprogram the proteome to enable lineage commitment. Yet, the developmental mediators of translational control and their mode-of-action remain elusive. Using human embryonic stem cells, we identified RBPMS as a vital translation specialization factor that allows selective translation of developmental regulators. RBPMS-driven translational control balances the abundance of cell-fate regulators to enable accurate lineage decisions upon receiving differentiation cues. RBPMS loss, without affecting pluripotency, specifically and severely impedes mesoderm specification and subsequent cardiogenesis. Mechanistically, the direct binding of RBPMS to 3’UTR allows selective translation of transcripts encoding developmental regulators including integral components of central morphogen signaling networks specifying mesoderm. RBPMS-loss results in aberrant retention of key translation initiation factors on ribosomal complexes. Our data unveil how emerging lineage choices from pluripotency are controlled by translational specialization via ribosomal platforms acting as a regulatory nexus for developmental cell fate decisions.IN BRIEFFuture lineage choices from pluripotency are controlled by translational specialization. The RNA binding protein RBPMS is a vital translational specialization factor that unlocks the mesoderm commitment potential of pluripotent stem cells by enabling selective translation of cell-fate regulators instructing lineage decisions.HIGHLIGHTSLineage choices emerging from pluripotency are selectively controlled by translational specializationThe RNA-binding protein RBPMS is a translation specialization factor dedicated to mesoderm commitmentRBPMS-driven translational specialization enables accurate lineage commitment via balancing the availability of key morphogen signaling componentsRBPMS loss selectively impairs mesoderm commitment and subsequently impedes cardiogenesisRBPMS binds the 3’UTRs of target mRNAs to allow their selective translation; its depletion leads to aberrant retention of key translation initiation factors on ribosomal complexes

scholarly journals The regulation of protein translation and its implications for cancer

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Ping Song ◽  
Fan Yang ◽  
Hongchuan Jin ◽  
Xian Wang
Keyword(s):  
Translation Initiation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Noncoding Rnas ◽  
Mrna Translation ◽  
Protein Translation ◽  
Initiation Factors ◽  
Translation Initiation Factors ◽  
Precision Therapy ◽  
Novel Approaches

AbstractIn addition to the deregulation of gene transcriptions and post-translational protein modifications, the aberrant translation from mRNAs to proteins plays an important role in the pathogenesis of various cancers. Targeting mRNA translation are expected to become potential approaches for anticancer treatments. Protein translation is affected by many factors including translation initiation factors and RNA-binding proteins. Recently, modifications of mRNAs mainly N6-methyladenine (m6A) modification and noncoding RNAs, such as microRNAs and long noncoding RNAs are involved. In this review, we generally summarized the recent advances on the regulation of protein translation by the interplay between mRNA modifications and ncRNAs. By doing so, we hope this review could offer some hints for the development of novel approaches in precision therapy of human cancers.

scholarly journals Genetic and structural analysis of the in vivo functional redundancy between murine NANOS2 and NANOS3

Development ◽  
2020 ◽  
pp. dev.191916
Author(s):  
Danelle Wright ◽  
Makoto Kiso ◽  
Yumiko Saga
Keyword(s):  
Germ Cell ◽  
Germ Cells ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Double Knockout ◽  
Germ Cell Differentiation ◽  
Evolutionarily Conserved ◽  
Male Specific

NANOS2 and NANOS3 are evolutionarily conserved RNA-binding proteins involved in murine germ cell development. NANOS3 is required for protection from apoptosis during migration and gonadal colonization in both sexes, whereas NANOS2 is male-specific and required for the male-type differentiation of germ cells. Ectopic NANOS2 rescues the functions of NANOS3, but NANOS3 cannot rescue NANOS2 function even though its expression is up-regulated in Nanos2-null conditions. It is unknown why NANOS3 cannot rescue NANOS2 function and it is unclear whether NANOS3 plays any role in male germ cell differentiation. To address these questions, we made conditional Nanos3/Nanos2 knockout mice and chimeric mice expressing chimeric NANOS proteins. Conditional double knockout of Nanos2 and 3 led to the rapid loss of germ cells, and in vivo and in vitro experiments revealed that DND1 and NANOS2 binding is dependent on the specific NANOS2 zinc finger structure. Moreover, murine NANOS3 failed to bind CNOT1, an interactor of NANOS2 at its N-terminal. Collectively, our study suggests that the inability of NANOS3 to rescue NANOS2 function is due to poor DND1 recruitment and CNOT1 binding.

scholarly journals Kinesin KIF18A is a novel PUM regulated target promoting mitotic progression and survival of human male germ cell line - TCam-2

2019 ◽  
Author(s):  
Maciej Jerzy Smialek ◽  
Bogna Kuczynska ◽  
Erkut Ilaslan ◽  
Damian Mikolaj Janecki ◽  
Marcin Piotr Sajek ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Germ Cell ◽  
Germ Cells ◽  
Posttranscriptional Regulation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Luciferase Reporter ◽  
Specific Gene ◽  
Transcriptional Level ◽  
Human Male

ABSTRACTRegulation of proliferation, apoptosis and cell cycle is crucial for the physiology of germ cells. Their malfunction contributes to infertility and germ cell tumours. Kinesin KIF18A is an important germ cell specific regulator which downregulates apoptosis while promoting cell proliferation in animal models. Whereas regulation of KIF18A expression was studied at the transcriptional level, its posttranscriptional regulation has not been extensively explored. Due to the presence of two PUM Binding Elements (PBEs) within 3’UTR, KIF18A mRNA is a potential target of PUMs, well known RNA-binding proteins involved in posttranscriptional gene regulation (PTGR). We investigated that possibility in TCam-2 cells originating from seminoma, representing human male germ cells. We conducted RNA co-immunoprecipitation combined with RT-qPCR, as well as luciferase reporter assay by applying appropriate luciferase construct encoding the wild type KIF18A 3’UTR, upon PUM1 and PUM2 overexpression or knockdown. We found that KIF18A is repressed by PUM1 and PUM2. To study how this regulation influences KIF18A function in TCam-2 cells, MTS proliferation assay, apoptosis and cell cycle, analysis using flow cytometry was performed upon KIF18A siRNA knockdown. We uncovered that KIF18A significantly influences proliferation, apoptosis and cell cycle, these effects being opposite to PUM effects in TCam-2 cells. We propose that repression by PUM proteins may represent one of mechanisms influencing KIF18A level in controlling proliferation, cell cycle and apoptosis in TCam-2 cells. To the best of our knowledge, this paper identifies the first mammalian functionally germ cell specific gene that is regulated by Pum proteins via 3’UTR.

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