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.
Department of Biological Sciences, Columbia University, New York, NY 10032, USA.
Ji
J
Li
Iva
I
Greenwald
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