germ line; totipotency; cell fate specification; C. elegans; mRNA regulation; mRNA translation; transdifferentiation
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
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Torres-Padilla Maria-Elena, Ciosk Rafal (2013), A germline-centric view of cell fate commitment, reprogramming and immortality., in Development (Cambridge, England)
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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
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Wright Jane E, Ciosk Rafal (2012), RNA-based regulation of pluripotency., in Trends in genetics : TIG
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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.
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.