RRC ID 59596
Author Shin H, Braendle C, Monahan KB, Kaplan REW, Zand TP, Mote FS, Peters EC, Reiner DJ.
Title Developmental fidelity is imposed by genetically separable RalGEF activities that mediate opposing signals.
Journal PLoS Genet
Abstract The six C. elegans vulval precursor cells (VPCs) are induced to form the 3°-3°-2°-1°-2°-3° pattern of cell fates with high fidelity. In response to EGF signal, the LET-60/Ras-LIN-45/Raf-MEK-2/MEK-MPK-1/ERK canonical MAP kinase cascade is necessary to induce 1° fate and synthesis of DSL ligands for the lateral Notch signal. In turn, LIN-12/Notch receptor is necessary to induce neighboring cells to become 2°. We previously showed that, in response to graded EGF signal, the modulatory LET-60/Ras-RGL-1/RalGEF-RAL-1/Ral signal promotes 2° fate in support of LIN-12. In this study, we identify two key differences between RGL-1 and RAL-1. First, deletion of RGL-1 confers no overt developmental defects, while previous studies showed RAL-1 to be essential for viability and fertility. From this observation, we hypothesize that the essential functions of RAL-1 are independent of upstream activation. Second, RGL-1 plays opposing and genetically separable roles in VPC fate patterning. RGL-1 promotes 2° fate via canonical GEF-dependent activation of RAL-1. Conversely, RGL-1 promotes 1° fate via a non-canonical GEF-independent activity. Our genetic epistasis experiments are consistent with RGL-1 functioning in the modulatory 1°-promoting AGE-1/PI3-Kinase-PDK-1-AKT-1 cascade. Additionally, animals lacking RGL-1 experience 15-fold higher rates of VPC patterning errors compared to the wild type. Yet VPC patterning in RGL-1 deletion mutants is not more sensitive to environmental perturbations. We propose that RGL-1 functions to orchestrate opposing 1°- and 2°-promoting modulatory cascades to decrease developmental stochasticity. We speculate that such switches are broadly conserved but mostly masked by paralog redundancy or essential functions.
Volume 15(5)
Pages e1008056
Published 2019-5-1
DOI 10.1371/journal.pgen.1008056
PMID 31086367
PMC PMC6534338
MeSH Animals Body Patterning / genetics Caenorhabditis elegans / genetics* Caenorhabditis elegans / growth & development Caenorhabditis elegans / metabolism Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism Epidermal Growth Factor / genetics* Epidermal Growth Factor / metabolism Epistasis, Genetic Female Fertility / genetics Gene Expression Regulation, Developmental* Guanine Nucleotide Exchange Factors / genetics* Guanine Nucleotide Exchange Factors / metabolism Receptors, Notch / genetics Receptors, Notch / metabolism Signal Transduction Stem Cells / cytology Stem Cells / metabolism Vulva / cytology Vulva / growth & development Vulva / metabolism* raf Kinases / genetics raf Kinases / metabolism ral GTP-Binding Proteins / genetics ral GTP-Binding Proteins / metabolism ras Proteins / genetics ras Proteins / metabolism
IF 5.224
Times Cited 0
C.elegans tm2760 tm5205 tm2255 tm6137