Trapping targets of dynamic translation to identify novel cellular “band aids”
Description: Translation is emerging as an important layer of gene expression control that enables rapid cellular responses to a changing environment. We recently demonstrated that limb amputation in the regenerative axolotl salamander triggers rapid activation of protein synthesis that appears to drive epithelial migration enabling seamless and rapid wound closure within hours of injury. However, the dynamics and targets of this translational remodeling are poorly understood, particularly within actively migrating epithelial cells central to this process. A major challenge to deciphering the role of translation in active cellular processes, such as epithelial migration observed in wound closure, is our fundamental inability to capture and analyze the distinct cell populations at the heart of this dynamic remodeling. This proposal will break new ground by exploiting the synergistic expertise of 4 labs (in axolotl regeneration and wound healing; in vivo quantitative imaging of translation and fly embryology; single-cell RNA and translation profiling; and spatial mass spectrometry on intact tissues) to reach a quantitative, multiscale understanding of translational control in two distinct paradigms of epithelia sheet migration: seamless closure of the wound site observed after limb amputation in the regenerative axolotl and dorsal closure in the embryonic fly. We hypothesize that movement of cellular sheets is supported by selective translation of specific mRNAs in cells at the leading edge. By applying our complimentary expertise, we will develop novel probes and advanced imaging techniques to quantify the kinetics of translation in living animals undergoing development (fly) and regeneration (axolotl). We will uncover the molecular signatures of actively migrating epithelial cells by applying novel single-cell translation profiling and “spatial mass spectrometry” approaches to decipher the molecular architecture of epithelial sheet migration and regenerative wound closure. Our combined expertise will enable us not only to define the conserved programs underlying epithelial migration across distinct species and cell contexts but also to uncover the identity and function of a repertoire of novel “band aid” proteins that drive wound healing in the regenerative axolotl for the first time.
Funder: Human Frontier Science Program
Amount: $1,500,000
Funding type: award
Start date: 2025-12-01
End date: 2028-11-30
Investigators: Olena Zhulyn, Mounia Lagha, Neil Kelleher, Alexander van Oudenaarden
Institutions: The Hospital for Sick Children, CNRS Languedoc-Roussillon, Northwestern University, Utrecht University (Universiteit Utrecht, UU)
Subfield: Molecular Biology
Domain: Life Sciences
Funded outputs count: 0
Funder award ID: RGP025/2025
OpenAlex ID: G3566047446