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Simple and Efficient Generation of Marked Clones in Drosophila

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Simple and Efficient Generation of Marked Clones in Drosophila Simple and efficient generation of marked clones in Drosophila Douglas A. Harrison and Norbert Perrimon” Harvard Medical School, Department of Genetics, and *Howard Hughes Medical Institute, 200 Longwood Avenue, Boston, Massachusetts 02115, USA. Background: Cell lineage analysis and mosaic analy- recombinase, under the control of a heat shock-in- sis of mutations are important techniques that are used ducible promoter, efficiently catalyses mitotic recombi- to study the development of many organisms. Unforhl- nation specifically at the site of a FLP recombination nately, the methods employed for such analyses are usu- target (FRT). In this system, recombination fuses the ally inefficient, technically demanding or labor intensive. a-tubulin promoter to the luGgene, allowing transcrip- In Drosophila, the most common methodology used for tion of the marker. Recombinant cells and their progeny the generation of mosaic animals is mitotic recombina- can, therefore, be detected by standard assays for p- tion, which is induced by X-rays. Although this technique galactosidase. Of particular importance is the fact that is simple, it has the undesirable characteristics of a low only the cells of interest stain, thus allowing their simple efficiency and a high rate of cell death. Furthermore, although a large number of marker systems has been detection in any tissue. employed to detect mitotic recombinants, none allows Conclusions: We demonstrate that, by intermolecular easy identification of clones for all cell types. recombination, we can use FLY recombinase to generate Results: A system is described here that allows a marked clones efficiently in embryonic, larval and adult highly efficient generation of clones with the concomi- tissues. This simple and efficient technique is well suited tant expression of an easily detectable cellular marker. to cell-lineage analysis and can be easily extended to This method can be applied to cell lineage and mo- the generation and detection of mutant clones in mosaic saic analysis in Drosophila The site-specific yeast FLP anitnals. Current Biology 1993, 3:424-433 Background by genetic techniques. Cell lineage has been most The ability to trace cellular lineages is critical to the extensively studied in the embryonic and adult epi- study of many developmental phenomena. Analysis of dermis, where a number of useful visible markers cell lineages allows us to determine the number of can be used to detect clones [3,14]. Animals mosaic cells that give rise to a given structure, the rates at for these markers have been generated by a variety which particular cell populations grow, and the origin of techniques, including nuclear transplantations and of the various cell types that form a tissue in the ma- genetically-induced loss of chromosomes [ 3,15,16]. ture animal. Unlike in Caenorbabditis eleguns, where IHowever, the technique most often used to induce mo- the origin *and destiny of all cells can be easily visu- saics in Drosophila is X-ray mitotic recombination. To alized [l], the cellular lineages of most animals can- generate recombination, an animal heterozygous for not be readily analysed. Many techniques have there- a recessive marker is eXpOSed to X rays dLu-ing cle- fore been developed to snake lineage analysis feasible veloptnent. X-irradiation induces chromosome breaks, in other organisms [2,3]. A straightforward approach which are sometimes repaired in such a way as to ex- that is used in many animals is the direct injection of change arms between homologous chromosomes. As high molecular weight dyes or histochemical markers a consequence, one of the daughter cells arising from into single cells of the embryo [&6]. Another method the recombinant mother will be homozygous for the that has been used is the generation of chimeric ani- marker, thus resulting in pdtches of mutant tissue in mals, such as chick-quail hybrids [ 71. An elegant tech- a wild-type animal. It is by using such techniques that nique currently used in some vertebrates involves injec- DrosoptMa fate maps were generated and the ‘coml’art- tion of replication-defective, histochemically-detectable ment hypothesis’ was formulated [I T--19] retroviral vectors into specific regions of the developing There are two major problems with the use of X- animal [S,S]. These approaches have led to significant irradiation for clonal induction. The typical dose of discoveries, such as observations indicating that the X-rays used in such experiments gives a low rate of specific fates of most vertebrate neural precursors are clone production and a high rate (4&60 %) of cell undetermined before the last mitotic division [l&12] lethality [ 201. Recently, these problems have been over- and that neural precursors arc able to migrate over come by using two different strategies that exploit the large distances [ 131. site-specific yeast recombinase, FLP. The first strategy In Dmopbila, lineage analysis has been accomplished uses mitotic exchange in much the same manner as X primarily through th? generation of mosaic animals rayinduced recombination [ 2 l--24], Two homologous Correspondence lo: Norbert Perrimon. 424 @ Current Biology 1993, Vol 3 No 7 Simple and efficient generation of marked clones in Drosophila Harrison and Perrimon RESEARCH PAPER 425 chromosomes carry a FLF’ recombination target site been possible to examine the roles of many essen- (FRT) at the same chromosomal position, with a mu- tial proteins in later developmental processes. For ex- tation on one homologue. FLP recombinase is then ample, this methodology uncovered the maternal role expressed under heat shock control and catalyzes the of the Drosophila raf kinase in the establishment of exchange of the chromosome arms specifically at the embryonic terminal structures [29]. FRTS,generating a patch of mutant tissue in an other- wise wild-type animal. A second strategy that could also Although the cuticle markers described above have be used for lineage analysis involves intramolecular re- been useful in the analysis of epidermis, they car- combination rather than chromosome exchange [ 251. not be employed for other tissues. Enzymatic mark- In the ‘flp-out’ technique, a constitutive promoter is ers, such as aldehyde oxidase, succinate dehydroge- fused to the lac Z gene that contains at the 5’ end nase and P-galactosidase, have been more generally a transcriptional stop sequence flanked by FRTs. Ex- used [3&32]. In conjunction with mitotic exchange, pression of FLP recombinase under heat shock control enzymatic markers have been used to create and mark results in the specific excision of the transcriptional mosaics in the internal tissues of the fly. However, addi- stop sequence by recombination occuring between the tional complexity is introduced because the marker is FRTs. This results in heritable activation of Lac Z in heterozygous in the animal before mitotic recombina- the recombinant cell lineage. These two FLPmediated tion. The result is that the entire animal, except for the systems avoid the drawbacks associated with X-rays. clone, stains positively for the marker. Consequently, The efficiency of FLP recombination is at least an or- the cells of interest are unstained within a background der of magnitude greater than X-rays and cell lethality of heterozygous cells that do stain. Although this is of is avoided because recombinase is expressed by heat relatively minor consequence in analysis of unicellu- shock, which does not affect cell viability. lar layers, it has made *analysis of internal tissues very difficult [31]. By extension of the mitotic exchange technique, it is Our goal was to develop a technique that uses efficient possible to create mosaic animals in which only some mitotic exchange to label clones heritably with an eas- cells are mutant for a gene of interest. Such an animal ily detectable marker, in a background that does not can be used to study the autonomy of gene function, express the reporter. In such a system, there would thus providing clues to the mechanism by which a gene be no staining for the marker in heterozygous cells; acts. For example, engraikd mutant cells exhibit cell therefore clones would be detected by the generation autonomy [ 261, whereas wingless mutant cells are non- of staining rather than by the loss of it, thus facilitating autonomous 1271. This is consistent with the molecu- analysis of both internal and external tissues. The tech- lar nature of engrailed protein as a transcription factor nique should be applicable to both cell-lineage analysis and wingless protein as a secreted signalling molecule and mosaic analysis of mutations. We describe such a [28]. Additionally, mosaics can be useful in analysing system that uses highly efficient, site-specific mitotic ex- the tissue-specific effects of zygotic lethal mutations as change catalysed by the FLP recombinase to reactivate it is possible to generate animals in which some tis- the expression of the LacZ gene by placing it dowr- sues are homozpgous for the lethal mutation. Mosaics stream of the a-tub&n promoter. We demonstrate that allow the analysis of the function of a gene product this system can be applied to cell lineage analysis and beyond the stage in development when a whole ani- describe how it can be extended to the mosaic analvsis mal of that genotype would die. In this manner, it has of most mutations. ----___~ (P-gal- , I FLP , o v’h Tub F I r\ I c Tub F Fig. 1. Summary of chromosome segregation associated with FLP-mediated mitotic exchange at 37°C. Chromosomes
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