The long-term goal of this project is to understand how embryos prevent and correct errors during early development, enabling them to develop normally in spite of challenges. It focuses on two aspects of early embryonic error correction, and uses zebrafish as a vertebrate model. First, how do embryos respond to and recover from DNA damage? Previous work identified a novel gene expression program that seems to be a response to DNA damage specifically in early embryos. Experiments will identify the conditions that activate this program, what happens to cells after its activation, and the role each gene plays in the program. Second, how do embryos recover from improper patterning? squint mutant embryos initially pattern too little mesendoderm due to reduced Nodal signaling, but they correct their patterning during gastrulation and develop into phenotypically normal adults. Experiments will test how patterning is extended in these mutants, where the rescued cells originate from, and then apply single-cell RNAseq to determine whether corrected cells differ long-term from wild-type cells.
These aims will show mechanisms used in embryos to correct patterning errors and respond to DNA damage, and determine whether error correction leaves persistent differences in the embryo. Lastly, these data will shed light on how some perturbations could result in partially penetrant birth defects and potentially suggest methods to reduce their penetrance.
Embryos often recover from damage or defects that occur in early development, but the mechanisms they use are not well understood. This project will study how embryos recover from DNA damage and mis-patterning, and will help understand how some birth defects arise and inform strategies to program cells to become specific tissues.
|Farrell, Jeffrey A; Wang, Yiqun; Riesenfeld, Samantha J et al. (2018) Single-cell reconstruction of developmental trajectories during zebrafish embryogenesis. Science 360:|