Notch-Dependent Fizzy-Related/Hec1/Cdh1 Expression Is Required for the Mitotic-to-Endocycle Transition in Drosophila Follicle Cells

Abstract

During Drosophila oogenesis, Notch function regulates the transition from mitotic cell cycle to endocycle in follicle cells at stage 6. Loss of either Notch function or its ligand Delta (Dl) disrupts the normal transition; this disruption causes mitotic cycling to continue and leads to an overproliferation phenotype. In this context, the only known cell cycle component that responds to the Notch pathway is String/Cdc25 (Stg), a G2/M cell cycle regulator. We found that prolonged expression of string is not sufficient to keep cells efficiently in mitotic cell cycle past stage 6, suggesting that Notch also regulates other cell cycle components in the transition. By using an expression screen, we found such a component: Fizzy-related/Hec1/Cdh1 (Fzr), a WD40 repeat protein. Fzr regulates the anaphase-promoting complex/cyclosome (APC/C) and is expressed at the mitotic-to-endocycle transition in a Notch-dependent manner. Mutant clones of Fzr revealed that Fzr is dispensable for mitosis but essential for endocycles. Unlike in Notch clones, in Fzr mutant cells mitotic markers are absent past stage 6. Only a combined reduction of Fzr and ectopic Stg expression prolongs mitotic cycles in follicle cells, suggesting that these two cell cycle regulators, Fzr and Stg, are important mediators of the Notch pathway in the mitotic-to-endocycle transition.

Atypical E2F activity restrains APC/C CCS52A2 function obligatory for endocycle onset

“…The CCS52A genes of Medicago sativa and Medicago truncatula have been shown to control the onset of endoreduplication during nodule development, and likewise, the CDH1 and FZR genes regulate the mitosis-to-endocycle transition in human and Drosophila cells, respectively (12)(13)(14)26). Arabidopsis has two CCS52A/FZR/CDH1-related genes, designated CCS52A1 and CCS52A2 (27).…”

“…At the molecular level, endoreduplication is likely achieved through elimination of the components needed to progress through mitosis (11). Predominant roles in this process are played by the anaphase-promoting complex/cyclosome (APC/C) activator genes, such as CDH1, FZR, and CCS52A, which have been found to promote endocycle onset and progression in human, Drososphila melanogaster, and Medicago truncatula cells, respectively (12)(13)(14)(15)(16)(17). The mechanisms controlling the transcriptional activity of these genes remain unclear, however.…”

New insights into cell cycle control from the Drosophila endocycle

“…Overexpression of fzr downregulates Cyclin A, Cyclin B and Cyclin B3, and inhibits mitosis. A role for Fzr in directing cells into the endocycle was first demonstrated in the wellstudied polytene nuclei of the larval salivary gland and has since been extended to other tissues (see below) (Sigrist and Schaeffer et al, 2004). Salivary gland nuclei from third instar larvae contain large polytene chromosomes that consist of over 2000 copies of the haploid genome.…”

“…Entry into the endocycle is accompanied by the transcriptional downregulation of many genes that promote mitotic progression including cyclin A, cyclin B, cyclin B3, Cdk1 and Cdc25/string (Smith and OrrWeaver, 1991;Sauer et al, 1995;Schaeffer et al, 2004). However, it is unlikely that this transcriptional inhibition is sufficient to trigger the mitotic/endocycle switch.…”

“…Several lines of evidence indicate that the proteolysis of the mitotic cyclins is essential for entry into a developmentally programmed endocycle. The mitotic cyclins are degraded by the highly conserved APC/C (Sigrist and Schaeffer et al, 2004). The APC/C is an E3 ubiquitin ligase that targets proteins for destruction by the 26S proteasome.…”