title: Cell-cycle regulation of NOTCH signaling during C. elegans vulval development.
abstract: C. elegans vulval development is one of the best-characterized systems to study cell fate specification during organogenesis. The detailed knowledge of the signaling pathways determining vulval precursor cell (VPC) fates permitted us to create a computational model based on the antagonistic interactions between the epidermal growth factor receptor (EGFR)/RAS/MAPK and the NOTCH pathways that specify the primary and secondary fates, respectively. A key notion of our model is called bounded asynchrony, which predicts that a limited degree of asynchrony in the progression of the VPCs is necessary to break their equivalence. While searching for a molecular mechanism underlying bounded asynchrony, we discovered that the termination of NOTCH signaling is tightly linked to cell-cycle progression. When single VPCs were arrested in the G1 phase, intracellular NOTCH failed to be degraded, resulting in a mixed primary/secondary cell fate. Moreover, the G1 cyclins CYD-1 and CYE-1 stabilize NOTCH, while the G2 cyclin CYB-3 promotes NOTCH degradation. Our findings reveal a synchronization mechanism that coordinates NOTCH signaling with cell-cycle progression and thus permits the formation of a stable cell fate pattern.
authors.affiliation: Institute of Molecular Life Sciences, University of Zürich, Zürich, Switzerland.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Nusser-Stein
authors.forename: Antje
authors.initials: A
authors.lastname: Beyer
authors.forename: Ivo
authors.initials: I
authors.lastname: Rimann
authors.forename: Magdalene
authors.initials: M
authors.lastname: Adamczyk
authors.forename: Nir
authors.initials: N
authors.lastname: Piterman
authors.forename: Alex
authors.initials: A
authors.lastname: Hajnal
authors.forename: Jasmin
authors.initials: J
authors.lastname: Fisher
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology* / Q000254:growth & development* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000378:metabolism*; D059447:Cell Cycle Checkpoints; D002454:Cell Differentiation; D002455:Cell Division; D019070:Cell Lineage; D016213:Cyclins / Q000378:metabolism; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008954:Models, Biological; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D051880:Receptors, Notch / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014844:Vulva / Q000166:cytology* / Q000254:growth & development*
chemical_list: D029742:Caenorhabditis elegans Proteins; D016213:Cyclins; C082460:Lin-12 protein, C elegans; D008565:Membrane Proteins; D051880:Receptors, Notch