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Translational control of totipotency in the animal germ line

English title Translational control of totipotency in the animal germ line
Applicant Ciosk Rafal
Number 133072
Funding scheme Project funding (Div. I-III)
Research institution Friedrich Miescher Institute for Biomedical Research
Institution of higher education Institute Friedrich Miescher - FMI
Main discipline Embryology, Developmental Biology
Start/End 01.01.2011 - 31.12.2013
Approved amount 375'000.00
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All Disciplines (3)

Discipline
Embryology, Developmental Biology
Genetics
Molecular Biology

Keywords (7)

germ line; totipotency; cell fate specification; C. elegans; mRNA regulation; mRNA translation; transdifferentiation

Lay Summary (English)

Lead
Lay summary
Germ cells, the cells that give rise to sperm and egg, have the potential to re-create all cell types in a new individual. This developmental flexibility of germ cells, also referred to as totipotency, needs to be tightly controlled. Perturbations in the mechanisms controlling totipotency can lead to unusual tumours called teratomas, in which germ cells differentiate into all types of somatic tissue and structures such as bone or teeth. The ability of germ cells to retain and control developmental flexibility is of great interest to both basic and applied research. To understand the molecular mechanisms that underlie and regulate totipotency we are using the invertebrate Caenorhabditis elegans as a genetically tractable and rapid model. Using this model, we have previously identified conserved RNA-binding proteins, GLD-1 and MEX-3, as key regulators of totipotency. By using a combination of genetics, functional genomics, and molecular biology, we will elucidate the precise function of these RNA regulators in controlling developmental flexibility of germ cells: dissect their mRNA targets, address how these targets are regulated, and examine how ectopic expression of target mRNAs affects cell fate reprogramming. In the long term, we may identify factors whose manipulation can induce cell fate reprogramming in differentiated somatic cells. This could have an impact on the treatment of degenerative diseases and cancer.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Name Institute

Employees

Publications

Publication
Structural and functional implications of the QUA2 domain on RNA recognition by GLD-1
Daubner GM, Brummer A, Tocchini C, Gerhardy S, Ciosk R, Zavolan M, Allain FH (2014), Structural and functional implications of the QUA2 domain on RNA recognition by GLD-1, in Nuclei Acids Research, 42(12), 8092-8105.
A germline-centric view of cell fate commitment, reprogramming and immortality.
Torres-Padilla Maria-Elena, Ciosk Rafal (2013), A germline-centric view of cell fate commitment, reprogramming and immortality., in Development (Cambridge, England), 140(3), 487-91.
Genome-Wide Analysis of GLD-1–Mediated mRNA Regulation Suggests a Role in mRNA Storage
Scheckel Claudia, Gaidatzis Dimos, Wright Jane, Ciosk Rafal (2012), Genome-Wide Analysis of GLD-1–Mediated mRNA Regulation Suggests a Role in mRNA Storage, in PLoS Genetics, 8(5), e1002742.
RNA-based regulation of pluripotency.
Wright Jane E, Ciosk Rafal (2012), RNA-based regulation of pluripotency., in Trends in genetics : TIG, 29, 99-107.
A quantitative RNA code for mRNA target selection by the germline fate determinant GLD-1.
Wright Jane E, Gaidatzis Dimos, Senften Mathias, Farley Brian M, Westhof Eric, Ryder Sean P, Ciosk Rafal (2011), A quantitative RNA code for mRNA target selection by the germline fate determinant GLD-1., in The EMBO journal, 30(3), 533-45.

Collaboration

Group / person Country
Types of collaboration
Eric Westhoff/BMC/CNRS Strasbourg France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Frederic Allain/ETH Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Sean Ryder/Univ. of Massachusetts Med. School, Worcester United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
DFG-Forschergruppen-Meeting ‘Posttranscriptional regulation of gene expression’ Talk given at a conference Posttranscriptional regulation of developmental plasticity 07.10.2013 Halle, Germany Ciosk Rafal;
Symposium on Chromosome Biology Talk given at a conference RNA-based regulation of developmental plasticity 20.10.2012 Oxford, Great Britain and Northern Ireland Ciosk Rafal;
EMBO symposium ‘Germline - Immortality through Totipotency’ Talk given at a conference REGULATION OF SELF RENEWAL AND DIFFERENTIATION IN THE GERM LINE 13.10.2012 Heidelberg, Germany Ciosk Rafal;
Arolla ‘Cell and Developmental Systems’ workshop Talk given at a conference RNA-based regulation of developmental plasticity 21.08.2012 Arolla, Switzerland, Switzerland Ciosk Rafal;
C. elegans Development, Cell Biology and Gene Expression Topic Meeting Talk given at a conference Genome-wide analysis of GLD-1 mediated mRNA regulation uncovers a role in mRNA storage 06.06.2012 Madison, USA, United States of America Ciosk Rafal;
The CSHL ‘Stem Cell Biology’ meeting Talk given at a conference Notch signaling antagonizes PRC2-mediated repression in C. elegans germ cells 21.09.2011 Cold Spring Harbor, United States of America Ciosk Rafal;
EMBO conference ‘Protein Synthesis and Translational Control’ Talk given at a conference Regulation of mRNA storage by the germline fate determinant GLD-1 07.09.2011 Heidelberg, Germany Wright Jane;
EMBO conference ‘Intracellular RNA Localization & Localized Translation’ Talk given at a conference Regulation of mRNA storage by the STAR protein GLD-1 08.08.2011 Il Ciocco, Italy, Italy Ciosk Rafal;
International C. elegans Meeting Talk given at a conference A quantitative RNA code for mRNA target selection by the germ line fate determinant GLD-1 21.06.2011 Los Angeles, United States of America Wright Jane;
Fondation Schlumberger, Réunion des Lauréats Talk given at a conference Regulation of mRNA storage by the germline fate determinant GLD-1 22.03.2011 Fondation des Treilles, France Ciosk Rafal;


Associated projects

Number Title Start Funding scheme
149402 Regulation of totipotency during animal development 01.09.2014 Project funding (Div. I-III)

Abstract

Maintenance of cell fate commitment by somatic cells is critical for the formation of complex biological structures such as the human body. Germ cells, in contrast, retain the potential to re-create all cell types in a new individual. This developmental flexibility of germ cells is also referred to as totipotency. Totipotency is critical to ensure species continunity. However, if the controls underlying totipotency are perturbed, this can lead to unusual germ cell tumours called teratomas. In a teratoma (from the Greek teras for a monster) germ cells differentiate into diverse types of somatic cells and structures such as bone or teeth. The ability of germ cells to retain developmental flexibility is of great interest to both basic and applied research. However, the molecular mechanisms that underlie and regulate totipotency are far from being understood. In the mammalian germ line, all evidence so far supports a multifactorial model of germ cell totipotency, and very few genetic components of teratoma formation have been identified. For these reasons, we have developed the first genetically tractable, rapid invertebrate model to study mechanisms controlling developmental potential of germ cells. We identified two conserved RNA regulators, GLD-1 and MEX-3, as key regulators of germline totipotency. In gld-1 mex-3 mutants, germ cells (trans)differentiate into all kinds of somatic cells, bypassing the normal program of oocyte formation and fertilization. For the purpose of this proposal we refer to this ‘worm teratoma’ as the germ line-to-soma transition (GST). GLD-1 and MEX-3 function as translational repressors, therefore abnormal expression of their target mRNA(s) in the germ line is thought to drive GST. Thus, identification of GLD-1/MEX-3 target mRNAs is expected to provide key insights into the factors and pathways regulating germ line totipotency.In contrast with the much-publicized transcriptional regulation of developmental flexibility, the role of posttranscriptional regulation has been all but neglected. This proposal has a unique focus on the translational control of totipotency. We will use C. elegans as an in vivo model to uncover the mechanims that control germline totipotency. We want to understand why GLD-1 and MEX-3 are crucial regulators of germ line totipotency, i.e. what are their relevant mRNA targets and what their de-repression does to unleash the developmental potential of germ cells. In addition, we want to understand how GLD-1 and MEX-3 regulate expression of their mRNA targets. Specifically, we will focus on the following problems: (1) Which mRNAs associate with GLD-1 and MEX-3? (2) Which mRNA targets are important for GST? (3) How do GLD-1 and MEX-3 regulate expression of their mRNA targets? (4) What are the molecular roles of GST regulators? (5) Do individual factors or pathways cooperate in controlling totipotency? Because GLD-1 and MEX-3 belong to conserved protein families whose members play many roles during development, we expect that the importance of our findings will extend beyond the C. elegans germ line. Also, as a germ cell is arguably the ultimate stem cell, our work is expected to provide important insights into the mechanisms regulating developmental flexibility in stem cells and regenerating cells.
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