Characterization of Hippo downstream effectors in the maintenance of planarian cellular identity

Abstract

[eng] The study of tissue renewal in adult organisms has widely been viewed as a source to uncover the triggers for the disruption of cell lineages in pathologies such as cancer. One of pathways involved in this process is the Hippo pathway. The Hippo pathway acts as a mechanosensor of extracellular physical forces. These inputs lead to the control of organ growth through the regulation of cellular fate. However, the exact mechanisms and biological processes that underly this maintenance of cellular fate remain elusive and require further characterization. One of this biological processes is cellular senescence. Cellular senescence has been linked with the onset of tumoral transformation and other age-associated disorders similar to dysregulations of the Hippo pathway. Other processes that share similarities with Hippo in regards to tumorigenesis include the regulation of cell cycle progression, cytoskeleton maintenance and transcriptional regulation. Nonetheless, the connection between the Hippo pathway and these biological processes have been poorly characterized so far. To better understand these mechanisms we use planarians (Schmidtea mediterranea). These are ageless flatworms able to regenerate any body part and constantly resize according to food availability. The aim of this thesis revolves around highlighting the importance of cellular senescence, transcriptomic and cytoskeletal regulation and cell cycle progression downstream of the Hippo pathway to properly maintain cellular differentiation in vivo. In order to assess the role of these biological processes we use a RNAi screening approach by inhibiting putative effectors of the pathway representative of these biological functions. All in all, we found that cellular senescence predates and contributes to the loss of cellular differentiation. Moreover senescence rescues are able to prevent such phenotype. Furthermore we show that defects in maintenance of the cytoskeletal architecture impair proper metaphase progression of the cell cycle and induce dedifferentiation. We also detect that deregulation in transcription also impairs the progression of the cell cycle and is associated with loss of cellular identity. Finally we also correlate defects in the progression of the cell cycle with proliferation and alterations in growth and degrowth dynamics according to the nutrient status of the planarian. In conclusion we affirm that the biological processes of cellular senescence, cytoskeletal maintenance, transcriptional regulation and cell cycle progression are linked with the Hippo molecular pathway and their physiological regulation are key for maintaining the cellular fate.