Journal of Cell Science 110, 523-528 (1997) 523 Printed in Great Britain © The Company of Biologists Limited 1997 JCS4371 COMMENTARY Cell cycle regulators in Drosophila: downstream and part of developmental decisions Christian F. Lehner* and Mary Ellen Lane† Department of Genetics, University of Bayreuth, 95440 Bayreuth, Germany *Author for correspondence (e-mail: [email protected]) †Present address: Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge MA 02142, USA SUMMARY The molecular identification of an evolutionarily conserved how the mitotic cycle is transformed into an endocycle set of cell cycle regulators in yeast, Xenopus egg extracts, which allows the extensive growth of larvae and oocytes. In and vertebrate cell culture has opened up a new perspec- contrast, we know little about cyclin/cdk regulation during tive for understanding the mechanisms that regulate cell the imaginal proliferation that generates the cells of the proliferation during metazoan development. Now we can adult. Nevertheless, we will also consider this second devel- study how the crucial regulators of eukaryotic cell cycle opmental phase with its conspicuous regulative character, progression, the various cyclin/cdk complexes (for a recent because it will be of great interest for the analysis of the review see Nigg (1995) BioEssays 17, 471-480), are turned molecular mechanisms that integrate growth and prolifer- on or off during development. In Drosophila, this analysis ation during development. is most advanced, in particular in the case of the rather rigidly programmed embryonic cell cycles that generate the Key words: Cyclin, cdk, Cell cycle, Development, Oogenesis, cells of the larvae. In addition, this analysis has revealed Endoreduplication THE EMBRYONIC CELL DIVISION PROGRAM destabilize maternal mRNAs including twine and string mRNA which encode partially redundant cdc25 phosphatases (Edgar Cell proliferation during Drosophila embryogenesis follows a and Datar, 1996). These maternal cdc25 transcripts are no defined program reflecting the developmental regulation of longer detectable after mitosis 13 (M13). The Cdc25string cyclin/cdk complexes. At the beginning of embryogenesis, protein, which is degraded during each mitosis just like A- and cyclin E/cdk2 (cdc2c) and A- and B-type cyclins in complexes B-type cyclins, and presumably the Cdc25twine protein as well, with cdk1(cdc2) are highly active and drive progression are also largely absent after their degradation in M13. Hence, through S and M phase, respectively. These complexes as well the early divisions stop. An additional division, however, is as all other components required for the initial nuclear division observed when the nucleo-cytoplasmic ratio is decreased (as in cycles are derived from maternal stores deposited in the egg in haploid embryos) or when the early zygotic transcription is quantities sufficient for more than thirteen cycles. Early inhibited (after α-amanitin injection). In the latter case, zygotic products, however, bring about a rapid removal of the maternal string and twine transcripts have been shown to maternal cdc25 provisions and make all subsequent divisions perdure and to be required for the extra division (Edgar and dependent on zygotic cdc25 production (Edgar and Datar, Datar, 1996). 1996, and references therein), since cdc25 phosphatase is indis- In contrast to cdc25, cyclin E/cdk2 and all other components pensable for the activation of the mitosis-promoting cdk1 required for S phase are still present after M13. This division, complexes. Both the onset of the early zygotic transcription therefore, is followed by an immediate progression into S causing the removal of maternal cdc25, as well as the zygotic phase (S14), as are previous and subsequent divisions of re-expression of cdc25, are precisely regulated by develop- embryogenesis. However, as a consequence of the removal of mental cues. It is this cdc25 regulation which dictates the the maternal cdc25 provisions, cells enter for the first time into embryonic division program. an extended G2 phase after completion of S14 and await The onset of the early zygotic transcription which results in zygotic cdc25string expression, which triggers progression the removal of maternal cdc25 is controlled by the nucleo-cyto- through M14 (Edgar et al., 1994). The onset of string tran- plasmic ratio. Beginning with cycle 10, an unidentified scription is dictated by the genes that specify positional infor- component becomes limiting for the exponential production of mation and developmental fate (patterning genes). Thus, cells nuclei. Thus, the rapid early cycles slow down, allowing the progress through M14 in a very dynamic spatial and temporal onset of early zygotic transcription. The first zygotic products pattern, which reflects the specification of the various devel- 524 C. F. Lehner and M. E. Lane opmental fates. Precisely regulated pulses of string transcrip- regulation of cyclin E expression (Knoblich et al., 1994) and tion also dictate the program of the subsequent divisions. This in parallel the up-regulation of the dacapo gene, which encodes complex transcriptional control of string is mediated by a very a CIP/KIP-type cdk inhibitor that functions as a cyclin E/cdk2 large upstream regulatory region that can be separated into inhibitor in vitro and presumably in vivo as well (de Nooij et distinct enhancer elements that direct transcription in defined al., 1996; Lane et al., 1996; for a review on cdk inhibitors, see cell types during particular cycles (Edgar et al., 1994). While Harper and Elledge et al., 1996). the string pulses are not affected by mutations blocking the cell In dacapo mutants, epidermal cells fail to enter G1 after M16 cycle, an alteration of the string expression pattern and conse- and instead continue through an additional cell cycle. Never- quently of the division program is caused by mutations in pat- theless, after the extra division, cells do not proliferate further, terning genes (Edgar et al., 1994), indicating that they provide but rather enter G1. The extra proliferation in dacapo mutants the predominant regulatory inputs for the string control region. is limited to one extra cycle because cyclin E and presumably It is obvious that an accurate temporal regulation of divisions other cell cycle regulators as well are down-regulated as in in development is of crucial importance whenever cell fates are wild-type embryos. The down-regulation of cyclin E (and other assigned with single cell precision. During CNS neurogenesis regulators) and the up-regulation of dacapo also occur when in Drosophila for instance, each neuroblast is specified as the cell cycle progression is arrested prematurely (Knoblich et al., founder of a specific, largely invariant lineage. No cell 1994; M. E. Lane and C. F. Lehner, unpublished). The divisions occur during the period when these individual processes that stop the embryonic cell proliferation, therefore, founder cells are specified within the ectodermal epithelium of are triggered whether or not the correct cell number has been the neurogenic region. Uncontrolled cell divisions during this reached (see also Busturia and Lawrence, 1994). The great selection process would probably result in frequent duplica- similarity of the patterns of dacapo and string transcript accu- tions of some of the neuroblast lineages. High accuracy is also mulation that is observed in the epidermis just prior to M16 a pre-eminent feature of Drosophila eye development. The raises the possibility that both genes are controlled by the same perfectly regular pattern of ommatidia is established in the developmental cues at this time. Thereby, progression through morphogenetic furrow that sweeps across the eye disc epi- the final mitosis is enforced by string, while dacapo ensures thelium during the larval and pupal stages. Cell divisions are that this terminal division is no longer followed by an strictly prevented in the morphogenetic furrow by a process immediate entry into S phase. that includes regulated string expression (Thomas and Zipursky, 1994; Heberlein et al., 1995). Such high precision processes are likely one reason why the intricate control of OOGENESIS AND ENDOREDUPLICATION string expression and mitosis has evolved. To what extent com- parable control is operating in vertebrate embryos is still Most of the postmitotic cells in Drosophila resume cell cycle unclear. progression, although not through mitotic but endocycles. The While mitosis must be inhibited for the sake of precise cell genome amplification resulting from these repeated rounds of fate specification in some instances, it might be required in S phase without intervening divisions allows extensive cell others. Cell specification in the neuroblast lineages, where an growth. The most dramatic cell growth, however, is observed exceptional number of different fates are specified often in oocytes. These cells have to undergo meiotic reduction and relying on asymmetric segregation and temporal regulation of cannot amplify the genome. But oocyte growth is nourished by determinants (Knoblich et al., 1995; Spana et al., 1995; Kraut nurse cells, which undergo extensive endoreduplication and are et al., 1996), reveals some cases where cell cycle progression intimately connected with the oocyte, and by follicle cells, is clearly indispensable for correct cell fate assignment which endoreduplicate and amplify the chorion genes. Ovaries, (Weigmann and Lehner, 1995; Cui and Doe, 1995),