Characterization of conserved post-transcriptional mechanisms regulating stem cells in planarians and mice

• Applicant: Professorin Dr. Kerstin Bartscherer
• Subject Area: Cell Biology ; Developmental Biology
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 266026236

• Final Report Year: 2019

Final Report Abstract

Plasticity describes the potential of a cell to change its state. This property poses a key challenge to biological systems: excess plasticity evokes disease, such as cancer, while too little prevents development or a fast response to environmental challenges. Which molecular circuits maintain a cellular state and how it is released upon demand is not well known. Pluripotency, after totipotency the most plastic cellular state and a fascinating phenomenon of early development, describes the potential of a stem cell to differentiate into all cell types of a multicellular organism. While research on pluripotency has focused on the regulation of gene expression by transcription factors and genome modifications, the contributions of posttranscriptional regulatory processes to the maintenance or induction of pluripotency, or the exit from it, have been largely neglected. Here, we used the planarian flatworm Schmidtea mediterranea, which possesses extraordinary regenerative abilities based on the presence of adult pluripotent stem cells, as a model organism for the regulation of pluripotent stem cells in vivo. Using RNA interference screening and RNA-sequencing based methods together with biochemistry and cell biology techniques we found that planarian stem cells use RNA-binding proteins (RBPs) for fine-tuning of generic cellular processes, such as mRNA splicing by the core spliceosome, to direct fate decisions. For instance, we could show that variants of UsnRNAs, uridyl-rich small nuclear RNAs, which are essential parts of the core spliceosome, are differentially expressed and processed in planarian stem cells when compared to differentiated cells. Disturbing the UsnRNA processing enzyme, the Integrator complex, results in alterations of the UsnRNA pool and stem cell splicing patterns, progressive loss of pluripotent stem cells, and lack of regeneration. Together with our yet unpublished findings that translational regulation of mRNAs by RBPs may play an important role in the maintenance of pluripotency and activation of regeneration, our study gives several new insights into how stem cell fate can be controlled in vivo by RBPs through modulation of posttranscriptional processes. Whether the uncovered mechanisms also play a role in the stem cells of the mouse is still under investigation.

Publications

• (2017). Generic wound signals initiate regeneration in missing-tissue contexts. Nat Commun 8:2282
  Owlarn S, Klenner F, Schmidt D, Rabert F, Tomasso A, Reuter H, Mulaw M, Moritz S, Gentile L, Weidinger G, and Bartscherer K
  
• (2018). PlanMine 3.0 - improvements to a mineable resource of flatworm biology and biodiversity. Nucleic Acids Res
  Rozanski A, Moon HK, Brandl H, Martin-Duran J, Grohme M, Hüttner K, Bartscherer K, Henry I, and Rink JC
  
• (2018). The Integrator complex regulates differential snRNA processing and fate of adult stem cells in the highly regenerative planarian Schmidtea mediterranea. PLoS Genet 14:e1007828
  Schmidt D, Reuter H, Hüttner K, Ruhe L, Rabert F, Seebeck F, Irimia M, Solana J, and Bartscherer K