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stumps, a Drosophila Gene Required for Fibroblast Growth Factor (FGF)-directed Migrations of Tracheal and Mesodermal Cells
Farhad Imam1,a, David Sutherland1,a, Wilmer Huanga, and Mark A. Krasnowaa Howard Hughes Medical Institute and Department of Biochemistry, Stanford University School of Medicine, Stanford, California 94305-5307
Corresponding author: Mark A. Krasnow, Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305-5307., krasnow{at}cmgm.stanford.edu (E-mail)
Communicating editor: R. S. HAWLEY
 | ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Fibroblast growth factors (FGFs) bind to FGF receptors, transmembrane tyrosine kinases that activate mitogenic, motogenic, and differentiative responses in different tissues. While there has been substantial progress in elucidating the Ras-MAP kinase pathway that mediates the differentiative responses, the signal transduction pathways that lead to directed cell migrations are not well defined. Here we describe a Drosophila gene called stumps that is required for FGF-dependent migrations of tracheal and mesodermal cells. These migrations are controlled by different FGF ligands and receptors, and they occur by different cellular mechanisms: the tracheal migrations occur as part of an epithelium whereas the mesodermal migrations are fibroblast-like. In the stumps mutant, tracheal cells fail to move out from the epithelial sacs, and only rudimentary tracheal branches form. Mesodermal cells fail in their dorsal migrations after gastrulation. The stumps mutation does not block all FGF signaling effects in these tissues: both random cell migrations and Ras-MAP kinase-mediated induction of FGF-specific effector genes occurred upon ectopic expression of the ligand or upon expression of a constitutively activated Ras protein in the migrating cells. The results suggest that stumps function promotes FGF-directed cell migrations, either by potentiating the FGF signaling process or by coupling the signal to the cellular machinery required for directed cell movement.
DIRECTED cell migration is required during the development of many tissues and is essential for proper immune system function and wound healing. Inappropriate cell migrations contribute to spreading of cancer cells throughout the body. Cell migrations occur by different cellular mechanisms, ranging from the crawling of isolated fibroblasts in culture to the coordinated movements of entire epithelial sheets during organ morphogenesis (
One FGF gene and two FGF receptor genes are known in D. melanogaster. The Branchless FGF is a ligand for the Breathless FGF receptor (
The Drosophila tracheal system is a ramified network of epithelial tubes that delivers oxygen throughout the body (
The Branchless FGF controls the early tracheal branching events (
In a screen for mutations that affect tracheal development, a mutation called stumps was discovered that caused a striking arrest in tracheal cell migration, resulting in a tracheal phenotype resembling that of null mutations in breathless (btl) or branchless (bnl;
| MATERIALS AND METHODS |
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| TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Fly strains and genetics:
The stumps1 mutation was identified by Dr. Christos Samakovlis in enhancer trap line l(3)9904 generated by A. Spradling and colleagues (
btlLG18 and btlLG19 (
2 (referred to as Df(3R)2; M. FULLER, personal communication), Df(3R)ry506-85C [derived from Tp(3;Y)ry506-85C (Flybase; http://flybase.bio.indiana.edu)], Df(3R)red1, Df(3R)ry85, and Df(3R)red3L (
Genetic mapping and cytology:
Meiotic recombination mapping crosses were carried out between the original stumps chromosome and the multiply marked rucuca chromosome, and between stumps1 and a cv-c P[w+, lacZ]0429 chromosome constructed by Dr. Julie Brill. Recombinants were scored for visible adult markers on the rucuca or cv-c P[w+, lacZ]0429 chromosomes and for the stumps tracheal phenotype. Recombination frequencies were analyzed in an F1 cross of w/w; stumps/cv-c P[w+, lacZ]0429 females to w; cv-c e males; the genotypes of 2617 F2 male progeny were determined.
For fine scale recombination mapping, several restriction fragment length polymorphisms (RFLPs) were identified in the 88C,D region using genomic DNA probes derived from P1 phage DS02646 (Berkeley Drosophila Genome Project; http://www.fruitfly.org) or from 
EMBL3 genomic phage (from J. Tamkun) that hybridized to P1 phage DS02646 (RFLPs 20-RT and 20-LT) and from genomic DNA flanking the P[w+, lacZ]3263 insertion (gift from J. Brill).
Preparation and orcein staining of salivary gland polytene chromosomes were carried out for stumps and Df(3R)2 as described (
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Immunohistochemistry and in situ hybridization:
Embryo fixation and staining, antibodies against tracheal antigens, ß-galactosidase, Engrailed, mAb 22C10, mAbBP102, and secondary antibodies have been described (
Ectopic expression of bnl and ras:
The Gal4/UAS expression system was used (
| RESULTS |
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| TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Genetic characterization and mapping of stumps:
In a screen of P[lacZ] enhancer trap lines, Christos Samakovlis discovered a line [l(3)9904] carrying a homozygous lethal mutation that almost completely blocked tracheal branching (Figure 1D), much like null (amorphic) mutations in the Breathless FGF receptor and Branchless FGF genes (Figure 1F). The mutation complemented btlLG18 and bnlP1 mutations for viability and mapped to a different chromosomal region, indicating that it defined a separate gene (see below). The gene was named stumps (2 or stumps/Df(3R)ry506-85C; Figure 1E)] was indistinguishable from that of the homozygote (Figure 1D), implying that stumps1 is a strong loss-of-function or null (amorphic) allele. Several other tissues examined were not grossly affected in the mutant. The overall structure of the embryo was normal, the segment polarity gene engrailed was expressed in its usual segmental stripes, and the peripheral nervous system (PNS) visualized with mAb 22C10 was unaffected (Figure 1H and data not shown). There were, however, defects in the central nervous system visualized by staining with mAbBP102 including increased separation, irregularities, and occasional breaks of the longitudinal connectives and fusions and irregularities in the transverse connectives (not shown). There were also gross defects in mesodermal development that are described in detail below.
The original stumps1 chromosome carried a P[ry+, lacZ] element at cytological position 82F8-9. However, chromosomal deficiencies that remove this region complemented the lethality and tracheal phenotype of stumps1, indicating that the stumps mutation was unlinked to the P[ry+, lacZ] insertion. The stumps1 mutation was localized to cytological interval 88D3-4 to 88D8 on the right arm of chromosome III by complementation tests with a set of chromosomal deficiencies that remove different regions of the chromosome (Figure 2B and Figure C). No cytological abnormalities were detected in this region of the stumps1 chromosome (Figure 2A), indicating that the mutation might be a small deletion or point mutation. Meiotic recombination mapping was used to localize stumps with respect to other genes in the region and to several RFLP markers that we identified. This analysis placed stumps 0.21 cM distal to crossveinless-c (cv-c) and 0.18 cM proximal to P[w+, lacZ]3263 (Figure 2D). For the rest of the experiments described here, we used a chromosome in which the P[ry+, lacZ] insertion and an unrelated lethal mutation had been recombined away from the stumps1 mutation (see MATERIALS AND METHODS).
stumps is required for tracheal cell migration:
Cellular and molecular markers were used to characterize the tracheal defects in the stumps1 mutant. The initial steps in tracheal development were normal in the mutant. The tracheal precursor cells invaginated to form the epithelial sacs at embryonic stage 11 (~6 hr AEL) and expressed the early tracheal markers trachealess (trh) and breathless normally (compare Figure 3A and Figure B, and data not shown). The initial activation of MAP kinase in the tracheal sacs by the EGF receptor pathway at stage 10 (
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During stages 13 and 14 (10–11 hr AEL), when secondary and terminal branch markers such as pointed (pnt), sprouty (spry), and DSRF have normally been induced by the Branchless FGF pathway in groups of cells at the ends of growing primary branches, only rare (pnt) or no (spry, DSRF) expressing cells were observed in stumps1 mutant embryos (Figure 3H and data not shown). Similarly, only sporadic tracheal cells showed staining with the antiserum specific for activated MAP kinase during stages 11–12, indicating that the Branchless signaling pathway was inactive or very weakly active in the trachea at this stage (Figure 3F). During stages 15–16 (12–15 hr AEL), when primary and secondary branching are complete and the first terminal branches are forming in wild-type embryos (Figure 1C), the tracheal sacs in stumps1 mutant embryos were still mostly unbranched with only an occasional rudimentary branch (Figure 1D).
stumps interacts genetically with branchless:
The tracheal phenotypes described above for the stumps mutant are very similar to those of null mutations in bnl and btl (
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Some downstream effects of Branchless FGF signaling can be activated in the stumps mutant:
Like bnl and btl mutations, the stumps mutation blocks tracheal cell migration and causes failure of MAP kinase activation, loss of induction of secondary and terminal branch markers, and failure to form secondary and terminal branches. This could mean that the Branchless signaling pathway is completely inactivated by the stumps mutation. Alternatively, the secreted signal might fail to diffuse properly and reach the tracheal cells, or the tracheal cells might receive the initial signal but fail to migrate toward the signaling source and thus never receive enough signal to trigger the later gene inductive responses. To test whether any downstream signaling effects of the Branchless pathway were intact in the stumps mutant, we ectopically expressed the Branchless FGF near the tracheal sacs and monitored the tracheal response.
The Gal4/UAS system was used to express Branchless in either the mesoderm of stumps1 mutants beginning at stage 6 or the tracheal cells themselves beginning at stage 11. Both conditions produced similar results. All of the later FGF signaling functions assayed were strongly activated in the portions of the tracheal sacs near the ectopic Branchless-expressing cells. MAP kinase was phosphorylated in these cells (Figure 5B), DSRF expression was induced (Figure 5E), and there was significant cytoplasmic outgrowth and ramification of terminal branches (Figure 5G). Some erratic outgrowth of primary branches also occurred (Figure 5G). Similar effects of ectopic Branchless expression were observed in Df(3R)2 homozygotes (not shown). We also obtained very similar effects when a constitutively activated Ras protein (Dras1V12) was expressed in the developing tracheal system of stumps1 mutants using a btlGal4 or a hsGal4 driver. Under these conditions too, downstream FGF signaling functions were activated in many or all tracheal cells (Figure 5C, Figure F, and Figure H), and there was erratic outgrowth of primary branches (Figure 5H). Thus, many downstream signaling events in the Branchless FGF signaling pathway can be activated in the stumps mutant upon ectopic expression of the ligand or by expression of an activated Ras. Interestingly, expression of the activated Ras in wild-type embryos did not disrupt the primary branching pattern, resulting only in ectopic induction of downstream genes and in extra terminal branching (Figure 5I and data not shown).
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stumps is required for mesodermal cell migration mediated by the Heartless FGF receptor:
In addition to the tracheal defects, the stumps1 mutant displayed a severe defect in mesodermal development. In wild-type embryos, mesodermal cells invaginate at the ventral midline at stage 6 (3 hr AEL) and migrate along the inner surface of the epidermis until reaching the dorsal margin of the epidermis two hr later at stage 10 (
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Although the tracheal phenotype of stumps mutant embryos is nearly identical to those shown by bnl and btl mutants, null mutants in these genes do not display any obvious mesodermal defects. The other known FGF receptor in Drosophila, however, encoded by heartless, is known to be expressed in and function in the developing mesoderm. Null htl mutations cause a mesodermal phenotype that is indistinguishable from that of the stumps1 mutant in every aspect in which they have been compared. This includes all of the morphological effects described above (
In the stumps1 mutant, as in null htl mutants, mesodermal cells failed to activate MAP kinase (data not shown), the dorsal mesodermal marker Tinman was only sporadically induced (Figure 6D), and the Even-skipped marker was never induced (Figure 7B). In htl mutants, the failure to induce the dorsal markers was shown to be a secondary consequence of the failure of most mesodermal cells to reach dorsal positions near the DPP inductive signal secreted by the dorsal-most ectodermal cells (
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We tested whether the mesodermal defects in stumps1 mutants could be ameliorated by expression of the constitutively activated Ras protein in the developing mesodermal cells using the same approach used to test for rescue of the tracheal defects. As in the tracheal system, expression of the activated Ras caused activation of MAP kinase and a general increase in motility, as well as induction of the dorsal muscle markers Even-skipped and Tinman (Figure 7D and data not shown). The effects of activated Ras in the stumps mutant were very similar to the reported effects of activated Ras in htl mutants (
| DISCUSSION |
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| TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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stumps is required for two distinct sets of embryonic cell migrations:
We have characterized the stumps1 mutant and shown that the gene is required for tracheal and mesodermal cell migrations. In the stumps mutant, tracheal precursor cells execute the initial steps of their morphogenetic program normally and invaginate to form epithelial sacs. However, the migrations of tracheal cells out from the sacs to form primary branches fail, and only an occasional stump ever develops. Similarly, the mesodermal precursor cells undergo the initial steps of their morphogenetic program normally, invaginating at the ventral midline to form the mesodermal primordium. The subsequent dorsal migrations of mesodermal cells fail, and the heart and other dorsal mesodermal derivatives are almost completely absent. Although many late tracheal and mesodermal processes fail in the stumps mutant, these may all be secondary to the migration failure because many of the later differentiative processes can be restored by ectopic expression of signaling pathway genes, as discussed further below. stumps does not appear to be a general factor required for cell migration because many other cell migrations, such as the endodermal migrations required to establish the gut, the neural migrations that form the PNS, and the spreading of the epidermal sheet during dorsal closure are all unaffected in the mutant. The two types of migrations that are affected do not have any notable properties in common with respect to migration mechanism, as the tracheal cell movements occur as part of an epithelium whereas the mesodermal migrations apparently occur by fibroblast-like movements. The only obvious shared feature of the two types of migrations affected by stumps is that both depend on FGF signaling pathways.
stumps functions in FGF signaling pathways:
Three lines of evidence support the hypothesis that stumps functions in FGF signaling pathways. First, the only two processes that are known to be affected in stumps mutant embryos are both dependent on FGF signaling pathways. The tracheal cell migrations require the Branchless FGF, which binds and activates the Breathless FGF receptor on tracheal cells and guides their migrations. Although the ligand for the mesodermal migrations is not known, these migrations require the Heartless FGF receptor, which is expressed specifically on the migrating cells. The tracheal and mesodermal migration defects observed in the stumps mutant are a virtual composite of those seen in null mutants of bnl or btl, and htl. No mutations in any other known genes cause a phenotype that so closely mimics either the bnl and btl phenotype or that of htl. Second, we observed dosage-dependent genetic interactions between bnl and stumps, as are often seen for genes in the same signaling pathway. The bnl FGF gene is haploinsufficient as bnlP1 heterozygotes show mild tracheal outgrowth defects (
Other cell migrations in Drosophila, such as glial cell migrations and border cell migrations in the ovary, also involve these two FGF signaling pathways (
Models of stumps function in FGF signaling and cell migration:
An important consideration with regard to the role of stumps in FGF-mediated tracheal migrations is that the gene does not appear to be required for all aspects of the tracheal FGF signaling pathway. All downstream effects of the Branchless FGF pathway we examined in addition to cell migration failed in the stumps mutant, including the activation of MAP kinase, the induction of secondary and terminal branching genes, and the formation of secondary and terminal branches. However, all of the gene inductive and differentiative effects could be restored by ectopic expression of the Branchless FGF or expression of the activated Ras. These treatments also induced some tracheal cell migration, although the migrations were limited in extent and did not follow the normal outgrowth pathways. Thus, the stumps1 mutant has the ability to generate an active FGF signal, receive the signal, and transduce it through MAP kinase and on to downstream target genes. The residual signaling capability is unlikely to result from leakiness of the stumps1 allele because stumps1 behaved as a null allele in genetic tests, and the same residual signaling capability was found in Df(3R)2 homozygotes that presumably lack the stumps locus.
Given that aspects of the FGF pathway are intact in the stumps mutant, including expression of the Branchless FGF and Breathless FGF receptor genes, we suggest two general models for how stumps may function in the tracheal FGF pathway. The first is that stumps acts as a potentiator in the pathway (Figure 8A). In this model, stumps is not absolutely required for any step in the process, but it is necessary to amplify or focus one or more steps. For example, it might facilitate transport or reception of the ligand, as heparan sulfate proteoglycans are believed to function in presenting the FGF ligand to FGF receptors in cultured mammalian cells (
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The second general class of models for stumps function requires a bifurcation in the FGF signaling pathway (Figure 8B). In these models, stumps is required only for one fork in the pathway—the fork needed for directed cell migration (guidance). The other fork would remain intact in the stumps mutant. Because MAP kinase activation and downstream effector genes were able to be induced in the stumps mutant, FGF signal production, reception, and this fork of the signal transduction pathway would be independent of stumps. General cell motility would also not require stumps, as tracheal cells in the stumps mutant could be induced to move, albeit erratically, upon ectopic expression of the Branchless FGF or expression of an activated Ras. Ectopic expression of activated Ras in the wild type did not perturb directed cell migration, demonstrating that the cells continued to receive the normal FGF guidance cues under these conditions. According to the bifurcating pathway models, all of the other FGF signaling failures observed in the stumps mutant would be secondary consequences of the tracheal cells' inability to follow the FGF signal toward its source and to receive continuous high levels of signal. Thus, if the signal were artificially brought close to the tracheal cells, as in our ectopic expression experiments, the mutant cells could respond normally in many respects, except for proper directional migration, just as was observed.
In the bifurcating pathway models, stumps functions downstream of the receptor. It might serve, for example, to mark the highest point of signaling activity on the membrane of the receiving cell and couple the activated receptor to the cytoskeletal machinery required for directed cell movement. Our data, however, do not allow us to place the split in the pathway with respect to Ras (or MAP kinase), as indicated by the alternative models diagramed in Figure 8B.
Although our analysis of the mesodermal migration defects in the stumps mutant was more limited because the ligand for the mesodermal FGF pathway is not known, the available data also fit well with a bifurcating signal transduction pathway. Mesodermal cells in the stumps mutant failed in their directed migrations, although they were still able to undergo limited, apparently random migrations. Expression of activated Ras stimulated motility and restored some dorsal mesodermal development. If the bifurcation model is correct (Figure 8B), it would suggest that the Heartless and Breathless FGF receptors use related signal transduction machineries to mediate directed cell migrations. Indeed, the intracellular portion of the Heartless FGF receptor can partially rescue defective tracheal outgrowth in a Breathless FGF receptor mutant, implying common downstream effectors in migration (
Many FGF receptors and other receptor tyrosine kinase pathways stimulate a variety of cellular effects including mitogenic, motogenic, and differentiative responses (, phosphoinositide-3' kinase, and Src have been implicated in signal transduction processes associated with migration (
| FOOTNOTES |
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1 These authors have contributed equally to this work. 
| ACKNOWLEDGMENTS |
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We are indebted to Dr. Christos Samakovlis who identified the original stumps mutation. We are also grateful to Dr. Julie Brill for valuable discussions and for strains and reagents in the 88D region and to Matt Fish for technical assistance. We thank Drs. S. Crews, D. Kiehart, E. Furlong, S. Roth, and A. Michelson for strains and antibodies, and the members of our lab for comments on the manuscript. This work was supported by a National Institutes of Health (NIH) grant (to M.A.K.) and NIH Medical Scientist Training Program fellowships to F.I. and D.S. M.A.K. is an investigator at the Howard Hughes Medical Institute.
Manuscript received October 22, 1998; Accepted for publication February 8, 1999.
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| NOTE ADDED IN PROOF |
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Complementation tests demonstrate that two recently described genes, Dof (VINCENT, S., R. WILSON, C. COELHO, M. AFFOLTER and M. LEPTIN, 1998, The Drosophila protein Dof is specifically required for FGF signaling. Mol. Cell 2: 515–525) and heartbroken (MICHELSON, A. M., S. GISSELBRECHT, E. BUFF and J. B. SKEATH, 1998, Heartbroken is a specific downstream mediator of FGF receptor signalling in Drosophila. Development 125: 4379–4389), are allelic to stumps.
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