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Regulation of totipotency during animal development

English title Regulation of totipotency during animal development
Applicant Ciosk Rafal
Number 149402
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 01.09.2014 - 31.08.2017
Approved amount 595'000.00
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All Disciplines (2)

Discipline
Embryology, Developmental Biology
Genetics

Keywords (5)

pluripotency; posttranscriptional regulation; stem cells; germ cells; development

Lay Summary (German)

Lead
Differenzierung und Reprogrammierung repräsentieren wichtige Ereignisse in der Entwicklung von Zellen und viele Krankheiten basieren auf Fehlern in diesen Prozessen. Unser Ziel ist es die molekularen Mechanismen aufzudecken, die die Pluripotenz kontrollieren. Dies ist von grossem Interesse für die Entwicklungsbiologie und die Stammzellforschung und hat mögliche Anwendungen für die regenerative Medizin.
Lay summary

Inhalt und Ziele des Forschungsprojektes

Es besteht ein spezieller Zusammenhang zwischen Keimzellen und Pluripotenz. Zum einen können sich Keimzellen zu pluripotenten Zelllinien entwickeln, zum anderen hat das Zytoplasma von Eizellen die Kapazität somatische Zellkerne zu reprogrammieren. Das Entwicklungspotenial der Keimzellen zeigt sich in einem Krankheitsbild bei dem die Keimzellen anstatt zu Spermien und Eizellen zu anderen somatischen Zelltypen reifen. Dieses Krankheitsbild wird als „Teratom“ bezeichnet. In der normalen Entwicklung haben nur Zellen im frühen Embryo die Möglichkeit sich zu jeder Art von Zelle zu entwickeln. Dies legt nahe, dass das Entwicklungspotential von Keimzellen bis nach der Befruchtung durch verschiedene Mechanismen unterdrückt wird. Unser Ziel ist es diese Mechanismen zu identifizieren und genauer zu analysieren.

Aufgrund des kurzen Lebenszyklus und der einfachen Handhabung arbeiten wir mit dem Fadenwurm Caenorhabditis elegans als Modellorganismus. Mit Hilfe eines genetischen Experiments haben wir das Protein LIN-41 als neuen Regulator der Pluripotenz in Eizellen identifiziert. Unser Ziel ist es die zu Grunde liegenden Mechanismen, wie etwa die relevanten Targets von LIN-41 zu beschreiben und somit die Interaktion von LIN-41 mit anderen Regulatoren der Pluripotenz zu verstehen.            

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojektes

Unsere Ergebnisse deuten darauf hin, dass LIN-41 das Entwicklungspotential der Eizellen unterdrückt und dazu beiträgt, dass der Übergang von einer Generation zur nächsten normal erfolgt. Dies ist das erste Beispiel eines solchen Regulators in Eizellen. Die meisten bekannten Regulatoren beeinflussen die Genexpression im Zellkern. Im Gegensatz dazu legen unsere bisherigen Forschungsergebnisse nahe, dass LIN-41 eine ähnliche Rolle im Zytoplasma spielt. Dies könnte wichtig sein im Bezug auf die Herstellung von humanen Stammzellen.
Direct link to Lay Summary Last update: 18.08.2014

Responsible applicant and co-applicants

Name Institute

Employees

Publications

Publication
LIN41 Post-transcriptionally Silences mRNAs by Two Distinct and Position-Dependent Mechanisms.
Aeschimann Florian, Kumari Pooja, Bartake Hrishikesh, Gaidatzis Dimos, Xu Lan, Ciosk Rafal, Großhans Helge (2017), LIN41 Post-transcriptionally Silences mRNAs by Two Distinct and Position-Dependent Mechanisms., in Molecular cell, 65(3), 476-489.
Functional characterization of C. elegans Y-box-binding proteins reveals tissue-specific functions and a critical role in the formation of polysomes.
Arnold Andreas, Rahman Md Masuder, Lee Man Chun, Muehlhaeusser Sandra, Katic Iskra, Gaidatzis Dimos, Hess Daniel, Scheckel Claudia, Wright Jane E, Stetak Attila, Boag Peter R, Ciosk Rafal (2014), Functional characterization of C. elegans Y-box-binding proteins reveals tissue-specific functions and a critical role in the formation of polysomes., in Nucleic acids research, 42(21), 13353-69.
The TRIM-NHL protein LIN-41 controls the onset of developmental plasticity in Caenorhabditis elegans.
Tocchini Cristina, Keusch Jeremy J, Miller Sarah B, Finger Susanne, Gut Heinz, Stadler Michael B, Ciosk Rafal (2014), The TRIM-NHL protein LIN-41 controls the onset of developmental plasticity in Caenorhabditis elegans., in PLoS genetics, 10(8), 1004533-1004533.
Structural and functional implications of the QUA2 domain on RNA recognition by GLD-1.
Daubner Gerrit M, Brümmer Anneke, Tocchini Cristina, Gerhardy Stefan, Ciosk Rafal, Zavolan Mihaela, Allain Frédéric H-T (2014), Structural and functional implications of the QUA2 domain on RNA recognition by GLD-1., in Nucleic acids research, 42(12), 8092-105.

Collaboration

Group / person Country
Types of collaboration
Fred Allain/ETH Switzerland (Europe)
- Publication
Attila Stetak/Biozentrum Uni Basel Switzerland (Europe)
- Publication
Peter Boag/Monash University Australia (Oceania)
- Publication
Helge Grosshans/FMI Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Basel Life Talk given at a conference Re-shaping a conserved RNA binding domain for distinct solutions to RNA binding specificity. 10.09.2017 Basel, Switzerland Kumari Pooja;
The Stem Cell Niche – development & disease Talk given at a conference The TRIM-NHL protein LIN-41 controls the onset of developmental plasticity in C. elegans. 22.05.2016 Hillerod, Denmark Ciosk Rafal;
International C. elegans meeting Talk given at a conference The CSR-1 endogenous RNAi pathway ensures accurate transcriptional reprogramming during the oocyte-to-embryo transition. 24.06.2015 Los Angeles, United States of America Fassnacht Christine;
Germ Cells Talk given at a conference The TRIM-NHL protein LIN-41 controls the onset of developmental plasticity in C. elegans. 07.10.2014 Cold Spring Harbor, United States of America Ciosk Rafal;


Self-organised

Title Date Place
Stem cells in development and disease 09.09.2014 Basel, Switzerland

Awards

Title Year
Honorable mention, The International C. elegans meeting 2017
Ruth Chiquet Originality Prize 2016

Associated projects

Number Title Start Funding scheme
133072 Translational control of totipotency in the animal germ line 01.01.2011 Project funding (Div. I-III)

Abstract

The molecular mechanisms underlying cell fate commitment and reprogramming are fundamental for development. A profound reprogramming takes place during reproductive (germ) cell development, which is why germ cells and the various pluripotent cell lines derived from them have been invaluable for dissecting the mechanisms controlling developmental plasticity, or totipotency. Ultimately, re-launching totipotency during the oocyte-to-embryo transition is critical for the life cycle to continue. The goal of this proposal is to elucidate the molecular mechanisms controlling totipotency during animal development. To do this, we have developed a genetically tractable, rapid invertebrate model to study mechanisms controlling developmental potential of germ cells. In contrast to the much-publicized transcriptional regulation of developmental plasticity, the role of posttranscriptional regulation has been largely neglected, despite the fact that the posttranscriptional regulation is essential during gametogenesis and the oocyte-to-embryo transition, i.e. at the stages when totipotency is unleashed. My previous research demonstrated that a conserved RNA-binding protein (RBP), GLD-1, is a key regulator of totipotency in the C. elegans germ line. In gld-1 mutants, germ cells abnormally differentiate into a variety of somatic cells. These cells form the invertebrate equivalent of a human germ cell tumor known as teratoma, in which germ cells differentiate into diverse types of somatic cells and structures such as bone or teeth. For the purpose of this proposal, we refer to this ‘worm teratoma’ as the germ line-to-soma transition (GST). In the past few years, my lab quantitatively dissected GLD-1 interactions with mRNA targets and described the effects of GLD-1 on the germline transcriptome. We also made a big step towards understanding the role of GLD-1 in controlling GST, providing a possible explanation for the etiology of teratomas. However, our understanding of the mechanisms controlling totipotency remains far from complete. One future goal is to understand the precise functions of GST regulatory proteins, including GLD-1 and a new factor recently identified in the lab, the TRIM-NHL domain protein LIN-41. This goal involves dissecting both the relevant targets of these proteins and the molecular mechanisms that they utilize. GLD-1 and LIN-41 are posttranscriptional regulators, but, somehow, they control transcriptional reprogramming. Thus, another goal is to understand the molecular connection between the posttranscriptional and transcriptional regulation in controlling GST. Finally, in order to understand the pathways controlling totipotency, the relationship between GLD-1 and LIN-41 will be examined.
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