Abstract
While many transcriptional regulators of pluripotent and terminally differentiated states have been identified, regulation of intermediate progenitor states is less well understood. Previous high throughput cellular resolution expression studies identified dozens of transcription factors with lineage-specific expression patterns in C. elegans embryos that could regulate progenitor identity. In this study we identified a broad embryonic role for the C. elegans OTX transcription factor ceh-36, which was previously shown to be required for the terminal specification of four neurons. ceh-36 is expressed in progenitors of over 30% of embryonic cells, yet is not required for embryonic viability. Quantitative phenotyping by computational analysis of time-lapse movies of ceh-36 mutant embryos identified cell cycle or cell migration defects in over 100 of these cells, but most defects were low-penetrance, suggesting redundancy. Expression of ceh-36 partially overlaps with that of the PITX transcription factor unc-30. unc-30 single mutants are viable but loss of both ceh-36 and unc-30 causes 100% lethality, and double mutants have significantly higher frequencies of cellular developmental defects in the cells where their expression normally overlaps. These factors are also required for robust expression of the downstream developmental regulator mls-2/HMX. This work provides the first example of genetic redundancy between the related yet evolutionarily distant OTX and PITX families of bicoid class homeodomain factors and demonstrates the power of quantitative developmental phenotyping in C. elegans to identify developmental regulators acting in progenitor cells.
Highlights
Identifying regulators of the intermediate steps that link pluripotency and terminal differentiation is a fundamental challenge in developmental biology
This occurs in large part by the expression of unique combinations of regulatory genes, such as transcription factors, in precursors of each cell type
The nematode worm Caenorhabditis elegans is a powerful system in which to identify developmental regulators because it has a rapid and reproducible development, yet it shares most of its developmental regulators with more complex organisms such as humans
Summary
Identifying regulators of the intermediate steps that link pluripotency and terminal differentiation is a fundamental challenge in developmental biology. These regulators are comparatively poorly understood for most tissues due to the difficulty of recognizing and isolating cells in these transient intermediate states (“progenitors”) and their complex combinatorial logic. Large-scale screens for gene pairs with synthetic phenotypes, as has been done for yeast [2] can identify genes acting in parallel, but screening at that scale is not feasible in animals We are overcoming these challenges with a systematic approach to define pleiotropic and redundant progenitor TFs in Caenorhabditis elegans, a simple model organism where lineage relationships are already understood, large-scale gene expression resources allow rapid identify patterns of TF overlap, and powerful tools exist for characterizing mutant phenotypes across all embryonic cells. Previous studies of genetic redundancy in C. elegans have prioritized gene pairs for synthetic lethality testing based on similar functional interactions [3,4], expression patterns [5] and homology or conservation [6,7]
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