Extensive remodeling of the translatome underlies tissue development and regeneration

My work reveals that regulation at the level of translation is an important new layer of gene expression control whichunderlies mammalian embryonic development and is a novel feature of vertebrate tissue regeneration. By applying cutting-edge methods to study translation at the organismal level for the first time, I uncover extensive evidence of translational regulation of core components of key signaling circuits, including SHH, Hippo and WNT. I demonstrate that this regulation is conferred in part throughcis-acting elements embedded in the untranslated regions of genes encoding key pathway components and is required to promote cell fate specification. Looking beyond development, I demonstrate that rapid activation of protein synthesis is a unique, previously uncharacterized feature of limb regeneration in the axolotl – a highly regenerative aquatic salamander. By applying polysome sequencing, I identify hundreds of transcripts, including antioxidants and ribosome components, which do not change in their overall mRNA abundance but are selectively activated at the level of translation from pre-existing mRNAs in response to injury. In contrast, protein synthesis is not activated in response to digit amputation in the non-regenerative mouse. Further, I identify the mTORC1 pathway as a key upstream signal that mediates this regenerative translation response in the axolotl and discover expansions in functionally critical regions of mTOR kinase that are unique to urodele amphibians and confer hypersensitivity on this kinase which may allow axolotls to maintain this pathway in a highly labile state primed for rapid activation and may underlie metabolic differences and nutrient sensing between regenerative and non-regenerative species that are key to regeneration. Together, these findings reveal the unanticipated impact of the translatome in diversifying gene expression across developing tissues and provide a missing link in our understanding of vertebrate regenerative potential. Dr. Olena Zhulyn is being interviewed as a candidate for the Scientist position at SickKids Research Institute