LIN-14 inhibition of LIN-12 contributes to precision and timing of C. elegans vulval fate patterning.
Studies of C. elegans vulval development have illuminated mechanisms underlying cell fate specification and elucidated intercellular signaling pathways [1]. The vulval precursor cells (VPCs) are spatially patterned during the L3 stage by the EGFR-Ras-MAPK-mediated inductive signal and the LIN-12/Notch-mediated lateral signal. The pattern is both precise and robust [2] because of crosstalk between these pathways [3]. Signaling is also regulated temporally, because constitutive activation of the spatial patterning pathways does not alter the timing of VPC fate specification [4, 5]. The heterochronic genes, including the microRNA lin-4 and its target lin-14, constitute a temporal control mechanism used in different contexts [6-8]. We find that lin-4 specifically controls the activity of LIN-12/Notch through lin-14, but not other known targets, and that persistent lin-14 blocks LIN-12 activity without interfering with the key events of LIN-12/Notch signal transduction. In the L2 stage, there is sufficient lin-14 activity to inhibit constitutive lin-12. Our results suggest that lin-4 and lin-14 contribute to spatial patterning through temporal gating of LIN-12. We propose that in the L2 stage, lin-14 sets a high threshold for LIN-12 activation to help prevent premature activation of LIN-12 by ligands expressed in other cells in the vicinity, thereby contributing to the precision and robustness of VPC fate patterning.
Li
Ji
J
Department of Biological Sciences, Columbia University, New York, NY 10032, USA.
Greenwald
Iva
I
D000818:Animals; D019521:Body Patterning / Q000502:physiology*; D017173:Caenorhabditis elegans / Q000196:embryology* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D005260:Female; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D009687:Nuclear Proteins / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D034622:RNA Interference; D051880:Receptors, Notch; D015398:Signal Transduction / Q000502:physiology*; D013696:Temperature; D019076:Transgenes / Q000235:genetics; D014844:Vulva / Q000166:cytology / Q000196:embryology*
D029742:Caenorhabditis elegans Proteins; D017931:DNA Primers; C102669:LIN-14 protein, C elegans; C082460:Lin-12 protein, C elegans; D008565:Membrane Proteins; D035683:MicroRNAs; D009687:Nuclear Proteins; D051880:Receptors, Notch; C452194:lin-4 microRNA, C elegans