BIOLOGICAL OVERVIEW

The morphogenetic furrow of the developing Drosophila eye provides a model system for studying the role of cell cycle genes and their control of cell proliferation and differentiation. A depression in the apical surface of the eye imaginal disc epithelium of the third instar larva, the morphogenetic furrow moves from the posterior region of the disc to the anterior. The passing of the furrow results in cell differentiation and in the induction of synchronous cell proliferation marked by the orderly expression of cell cycle genes.

Prior to the passing of the furrow there are many S phase and mitotic cells expressing Cyclin A and Cyclin B. Initially, a domain of string expression occurs, prior to the passing of the furrow, found in a narrow band of cell roughly 5- to 6-cell diameters wide. Cyclin D expression reaches high levels immediately after the induction of string. The string domain represents a transition point: S phase ceases at its anterior boundary, expression of Cyclin A and Cyclin B terminates, and an increase in cells in mitosis is seen within the string domain (Thomas 1994). Significantly, the band of Cyclin D expression occurs before cells reenter into the cell cycle. Cyclin E is expressed posterior to the band of Cyclin D expression, in a region partially overlapping the synchronous band of S-phase cells (Thomas 1994).

What is the function of string and Cyclin D expression ahead of the developing furrow? The expression of string is accompanied by an increase in the number of cells in mitosis as would be expected if the function of string were to drive cells in G2 into a round of mitosis. This increase in density of mitotic activity represents a two fold increase over the number seen in the unpatterned region anterior to the furrow (Thomas, 1994).

Cells in G1 are inhibited from entering S phase. Thus some aspect of cell cycle regulation inhibits passage into S for a certain period of time. The occasional S phase cells seen overlapping the anterior edge of STG mRNA suggests that cells already in S phase complete it before progressing into G2. One gene involved in regulation of the G1 phase is roughex. Mutations in roughex cause cells to circumvent G1, and all cells enter S phase, including cells that would normally differentiate. This leads to defects in early steps of pattern formation and cell fate determination.

The G1 period is accompanied by cell shape changes that define the furrow and marks the beginning of cluster differentiation. In the midst of the furrow, cellular interactions play a role in restricting the number of R8 cells that form within the morphogenetic furrow to one per cluster. At the posterior edge of the morphogenetic furrow, cells are formed into regularly spaced preclusters that contain postmitotic precursors serving as the first five photoreceptor cells to differentiate, R8 and R2-5. Following an extended G1 period, marked by Cyclin D and Cyclin E expression and the passing of the furrow, the remaining cells pass synchronously into S phase (following the passage of the furrow) and then into G2 and M, accompanied by the expression and degradation of Cyclins A and B. The expression of Cyclin D and E prior to the passing of the furrow set the stage for the cycle of synchronous division in the cells that do not immediately differentiate. Paradoxically, although all cells passing through the furrow express Cyclin D and Cyclin E, only a fraction of those cells undergo the synchronized division that follows the passing of the furrow (Thomas, 1994 and Finley, 1996).

PROTEIN STRUCTURE

Amino Acids - 452

Structural Domains

Drosophila Cyclin D shows strongest similarity to cyclins in a 135 amino acid region, extending from residue 157 to residue 292. This region contains matches to the 20 most conserved residues of most cyclins. The first 97 amino acids contain PEST sequences involved in rapid protein turnover. Drosophila Cyclin D is 39% identical to human Cyclin D2 but is only 18 to 24% identical to the other classes of cyclins identified either in humans or Drosophila. The consensus Cyclin D sequence consists of 65 residues, of which 24 are unique to D cyclins (Finley, 1996).

date revised: 6 Jan 96 

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