Decoding lineage and fate specification in the C. elegans embryo

ABSTRACT Single cell approaches to measure gene expression genome-wide across all cells of developing organisms are beginning to revolutionize our study of development, but we are still learning how to maximize the use of single cell “atlases” and related methods to learn new developmental mechanisms. The C. elegans embryo is an ideal system for single cell approaches because of its invariant development and powerful experimental tools., and the conservation of major regulatory mechanisms with humans. We have developed large-scale expression resources to learn the “parts list” of embryonic fate specification. These include a single-cell RNA- seq atlas of gene expression across most embryonic cells as well as protein expression profiles of hundreds of transcription factors in the “Expression Patterns in Caenorhabditis” (EPIC) database that contains the expression of over 250 fluorescent reporters analyzed by automated lineage tracing and expression mapping methods. This proposal aims to understand the zygotic regulation of lineage specification during the period from ~gastrulation through terminal differentiation. This critical developmental period was previously hard to study due to redundancy and complex phenotypes, but our pioneering work combining single cell approaches with mechanistic reverse genetics is helping to overcome these hurdles. Our recent and proposed work aims 1) to improve the utility, interpretability and quality of single cell embryonic atlases, 2) to leverage whole- organism approaches to understand developmental regulatory networks, especially the context-specific ability of the Wnt pathway to regulate lineage-specific targets, and 3) to understand how dynamic processes like high- rate transcription and RNA turnover control the robust, timely, regulation of developmental decisions. This work will both extend our understanding of developmental mechanisms, and provide lessons for similar studies in more complex animals.