title: The mitotic-to-endocycle switch in Drosophila follicle cells is executed by Notch-dependent regulation of G1/S, G2/M and M/G1 cell-cycle transitions.
abstract: The Notch signaling pathway controls the follicle cell mitotic-to-endocycle transition in Drosophila oogenesis by stopping the mitotic cycle and promoting the endocycle. To understand how the Notch pathway coordinates this process, we have identified and performed a functional analysis of genes whose transcription is responsive to the Notch pathway at this transition. These genes include the G2/M regulator Cdc25 phosphatase, String; a regulator of the APC ubiquitination complex Hec/CdhFzr and an inhibitor of the CyclinE/CDK complex, Dacapo. Notch activity leads to downregulation of String and Dacapo, and activation of Fzr. All three genes are independently responsive to Notch. In addition, CdhFzr, an essential gene for endocycles, is sufficient to stop mitotic cycle and promote precocious endocycles when expressed prematurely during mitotic stages. In contrast, overexpression of the growth controller Myc does not induce premature endocycles but accelerates the kinetics of normal endocycles. We also show that Archipelago (Ago), a SCF-regulator is dispensable for mitosis, but crucial for endocycle progression in follicle epithelium. The results support a model in which Notch activity executes the mitotic-to-endocycle switch by regulating all three major cell cycle transitions. Repression of String blocks the M-phase, activation of Fzr allows G1 progression and repression of Dacapo assures entry into the S-phase. This study provides a comprehensive picture of the logic that external signaling pathways may use to control cell cycle transitions by the coordinated regulation of the cell cycle.
authors.affiliation: Department of Biochemistry, University of Washington, J591, HSB, Seattle, WA 98195-7350, USA.
authors.forename: Halyna R
authors.initials: HR
authors.lastname: Shcherbata
authors.forename: Cassandra
authors.initials: C
authors.lastname: Althauser
authors.forename: Seth D
authors.initials: SD
authors.lastname: Findley
authors.forename: Hannele
authors.initials: H
authors.lastname: Ruohola-Baker
mesh_terms: D000818:Animals; D064200:Cdh1 Proteins; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D056741:Cyclin D; D019927:Cyclin E / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D003598:Cytoskeletal Proteins; D015536:Down-Regulation; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D016193:G1 Phase; D016195:G2 Phase; D008565:Membrane Proteins / Q000378:metabolism*; D008938:Mitosis; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism; D006080:Ovarian Follicle / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D051880:Receptors, Notch; D016196:S Phase; D015398:Signal Transduction; D013696:Temperature; D013997:Time Factors; D020687:cdc25 Phosphatases / Q000378:metabolism
chemical_list: D064200:Cdh1 Proteins; D018797:Cell Cycle Proteins; C534694:CycD protein, Drosophila; D056741:Cyclin D; D019927:Cyclin E; D016213:Cyclins; D003598:Cytoskeletal Proteins; D029721:Drosophila Proteins; D008565:Membrane Proteins; C497759:N protein, Drosophila; C120529:NDC80 protein, human; D009687:Nuclear Proteins; D051880:Receptors, Notch; C103336:dap protein, Drosophila; C577674:fzr protein, Drosophila; D017027:Protein Tyrosine Phosphatases; D020687:cdc25 Phosphatases; C059217:stg protein, Drosophila