Academic journal article Genetics

The Chromatin-Remodeling Protein Osa Interacts with CyclinE in Drosophila Eye Imaginal Discs

Academic journal article Genetics

The Chromatin-Remodeling Protein Osa Interacts with CyclinE in Drosophila Eye Imaginal Discs

Article excerpt

ABSTRACT

Coordinating cell proliferation and differentiation is essential during organogenesis. In Drosophila, the photoreceptor, pigment, and support cells of the eye are specified in an orchestrated wave as the morphogenetic furrow passes across the eye imaginal disc. Cells anterior of the furrow are not yet differentiated and remain mitotically active, while most cells in the furrow arrest at G1 and adopt specific ommatidial fates. We used microarray expression analysis to monitor changes in transcription at the furrow and identified genes whose expression correlates with either proliferation or fate specification. Some of these are members of the Polycomb and Trithorax families that encode epigenetic regulators. Osa is one; it associates with components of the Drosophila SWI/SNF chromatin-remodeling complex. Our studies of this Trithorax factor in eye development implicate Osa as a regulator of the cell cycle: Osa overexpression caused a small-eye phenotype, a reduced number of M- and S-phase cells in eye imaginal discs, and a delay in morphogenetic furrow progression. In addition, we present evidence that Osa interacts genetically and biochemically with CyclinE. Our results suggest a dual mechanism of Osa function in transcriptional regulation and cell cycle control.

ALTHOUGH much has been learned about the mechanisms that regulate the cell cycle and assign particular fates to cells, little is known about the processes that coordinate cell number and cell type (for review see Zhu and Skoultchi 2001). Drosophila eye development offers an attractive system for investigating how these processes are coregulated. The Drosophila compound eye is formed by a mono-layered epithelium whose cells divide continuously in an undifferentiated state during most of the three larval instar stages. During late larval and early pupal development, cells that commit to neuronal photoreceptor, pigment, and support-cell fates permanently exit the cell cycle. The transformation is precisely coordinated in space and time as a wave of differentiation passes across the epithelium. This wave is marked by an indentation called the morphogenetic furrow (MF) that traverses the disc from posterior to anterior. Posterior to the MF, cells that undergo neural differentiation arrest in G1, while uncommitted cells reenter the cell cycle for one last round of division, forming a band-like second mitotic wave (SMW) (Wolff and Ready 1993; Baker 2001, 2007). Grouping these various types of cells into the precisely arranged ommatidia requires that the different cell types be produced in appropriate numbers and ratios. The rapid transition from proliferation to differentiation that occurs at the MF offers an opportunity for investigating the mechanisms that regulate the balance between proliferation and differentiation.

In multicellular animals, the G1-to-S-phase transition is regulated by the G1 cyclins, CyclinD and CyclinE (CycE), which activate Cyclin-dependent-kinases (Cdks). In Drosophila, the activity of the CycE-Cdk2 complex is both sufficient and rate limiting for the G1-to-S-phase transition (Knoblich et al. 1994; Richardson et al. 1995; Sauer and Lehner 1995; Secombe et al. 1998). A critical target of these kinases is the Retinoblastoma (Rb) tumor suppressor protein (reviewed in Ekholm and Reed 2000). Rb phosphorylation by Cdk causes the activation of the E2F/DP transcription factors that activate expression of S-phase-promoting genes. While cross-regulation between E2F activity and CycE contributes to the coordination of G1-to-S-phase transition and exit from the cell cycle upon terminal differentiation, genetic analysis has suggested that additional mechanisms contribute to the cell cycle arrest (Buttitta et al. 2007).

One additional mechanism is provided by the function of Dacapo (Dap), a member of the CIP/KIP family of Cdk inhibitors. In eye imaginal discs, dap expression is activated by EGFR and Hedgehog (Hh) signaling in post-mitotic cells in and posterior to the MF (Lane et al. …

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