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Departments of Pediatrics, Section of Respiratory Medicine, and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520
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Drosophila melanogaster has been used as a genetic model, especially in the past decade, to examine normative biological processes and disease conditions very effectively. These span a wide range of major issues such as aging, cancer, embryogenesis, neural development, apoptosis, and alcohol intoxication. Here, we detail how the Drosophila melanogaster can be used as a genetic model to study the molecular and genetic underpinnings of the response to hypoxia. In our study of the basis of anoxia tolerance, one of the potent approaches that we use is a mutagenesis screen to identify loss-of-function mutants that are anoxia sensitive. The major advantage of this approach is that it is not biased for any particular gene or gene product. Although our screen is in progress, we already have evidence that this approach is useful.
central nervous system; differential display; genetics and reverse genetics; anoxia; invertebrate models
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A SIMPLE PubMed database search reveals that, since the mid 1970s, ~1,000 articles are written per year on the subject of hypoxia. Clearly, a variety of subject topics are addressed at a variety of levels, from an integrative to a molecular level. Although this number of publications does not rival the number of articles written, say, for AIDS, many investigators over the past century have been interested in hypoxia.
The reasons for this interest in the subject are varied but can be grouped into two main categories: 1) an interest in how an individual (from yeast to humans) responds to low O2 conditions and how the adaptation to such a stress takes place and 2) interest in mechanisms that lead to cellular and tissue injury and repair. Indeed, in the past two to three decades, a plethora of new ideas has surfaced and this whole field has been exciting, especially because the scientific community involved in this field is multidisciplinary with varied backgrounds.
From all of these studies, therefore, we have learned a great deal. For example, there are many events that follow O2 deprivation, inside and outside cells, that can impact on cell function. Furthermore, there are a number of cellular mechanisms that are activated that allow survival if the stress is not too severe. However, there comes a point in the cascade of events at which irreversible injury sets in, if the stress persists. This injury can also lead to either necrosis or apoptosis. Finally, a large number of molecules are involved in these responses, including, ion channels, neurotransmitters, growth factors, cytoskeletal proteins, lipases and proteases, and transcription factors. Some of these will differ depending on whether the stress is of acute or of chronic onset.
There are still, however, many questions that have no answer. For example, we do not know what is the exact role of each event in the overall scheme of the response to low O2. What is the importance of the downregulation in metabolic rate during hypoxia in some individuals and species and how does one assess its role (10-12, 31)? What is the importance of the increase in intracellular Ca2+ during hypoxia (6)? What is the importance of the opening of K+ channels during hypoxia in nerve cells (5, 7, 8, 14-18, 35)? What is the importance of the activation of a number of intracellular kinases during cellular hypoxia (29)? And what is the role of the increase or decrease in a variety of neurotransmitters and growth factors during lack of O2 (10, 25, 36)? Of course, all of these questions have some answers, mostly speculative, sometimes teleologically reasonable, but often without hard evidence. Another example is also very interesting: we do not fully understand the basis of the wide heterogeneity in the response to lack of O2 between organisms, between organs of the same individual, or between cell types of the same organ. Consider the vast difference between the rat and the turtle in terms of their cellular responses to hypoxia (10)! Consider the much greater resistance to the lack of O2 in the newborn mammal vs. the adult or mature animal (9). Consider the differences in the responses to hypoxia between different regions of the central nervous system (CNS), such as the neocortex, the hippocampus, and the brain stem (5)! And consider the differences even between subregions of the CNS and cell types differences such as in the hippocampus and dentate gyrus (20).
Although some of these questions are readily answerable in mammalian systems, others are not. Several years ago, while pondering some of these questions, we elected to delve into a genetic model and try to answer some of these questions in the Drosophila melanogaster. The experiments that we performed on this model and that are described below took place after we had worked with a variety of mammals and organisms, including rodents (neonates and mature) and turtles, to address some of the questions posed above.
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WHY GENETIC MODELS AND WHY DROSOPHILA? |
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Because we were convinced that the differences detailed above could be explained, at least in part by inheritance, we considered a number of potential genetic models for use. In addition, there were two major questions that we were very interested in at that particular juncture: 1) What is the genetic basis for the wide heterogeneity in the response to lack of O2? 2) Can we use anoxia-tolerant organisms to understand the basis of O2 responsiveness? It was also clear to us at that time that the freshwater turtle that was considered the par excellence model for an anoxia-tolerant organism was not an optimal organism, if cutting-edge molecular techniques were to be employed. Furthermore, although some mammalian tissues were much more tolerant to lack of O2 than others (3, 4, 10) and these tissues could be used and worked on to analyze the basis for anoxia tolerance, laboratory mammals in general, such as rodents, were not going to be easy to experiment with from a genetic point of view. Hence, we resorted to other organisms. Because we found that the zebrafish and the goldfish were not tolerant to anoxia, these became less useful to us. It is at that time that we discovered that the Drosophila melanogaster was resistant to lack of O2 (19).
When Drosophila flies are subjected to extremely low
O2 concentrations (
0.01%) and when their physiological
and behavioral responses are studied before, during, and after anoxia,
they show a very interesting phenomenon. When they are first exposed to anoxia (complete lack of O2), Drosophila lose
coordination, fall, and become motionless after ~30-60 s in
anoxia (and depending on the N2 flow). However, they
tolerated a complete N2 atmosphere for several hours,
following which they seemed to totally recover without apparent injury
and with the ability to mate, fly, and see normally. Of interest, mean
O2 consumption per gram of Drosophila tissue is
substantially reduced at low O2 concentrations (20% of
control) (13, 19). It is very interesting to note that the resistance
to anoxia can be manifested differently in different organisms. For
example, Drosophila definitely senses the lack of
O2, as it responds quickly in a way similar to mammals;
i.e., these flies develop anoxic stupor when the O2 level
is very low (13, 19). In addition, they show a physiological response that is commensurate with this behavioral response. Indeed,
extracellular recordings from flight muscles in response to giant fiber
stimulation (a well-characterized nerve-muscle system and connections)
reveal that, within a very short period, muscle-evoked potentials are totally silenced with anoxia (13, 19). Furthermore, there is a complete
recovery of muscle-evoked potentials with reoxygenation, after a
latency that is proportional to the anoxic period, a physiological response that is again similar to the behavioral one. This
stereotypical response in flies is very different from that in turtles.
Turtles do not seem to lose neuronal activity, even after very
prolonged anoxia (10, 34), extending to hours. Hence, flies, unlike turtles, seem to have different strategies for survival under very
low-O2 conditions. From the point of view of sensing, flies seem to behave phenotypically in a manner that is similar to mammals, since they sense the low-O2 conditions and respond to it
like mammals (13, 19). However, flies seemingly do recover from prolonged anoxia, but this is not the case in mammalian organisms and
tissues. Hence, the question is how can flies (and other organisms capable of tolerating anoxia) recover from anoxia and survive the
severe stress?
Although some of the genetic models, including Drosophila, have been in use for many decades, the conservation of complements of genes with evolution, from prokaryotes to eukaryotes and from yeast, Drosophila, Caenorhabditis elegans, zebrafish to humans, has become more appreciated in the past decade. With this important discovery of gene conservation, these models have become even more timely and useful in trying to solve problems relevant to human physiology, biology, and disease. Genes responsible for functions as varied as circadian rhythms, aging, alcohol intoxication, and development of tracheal buds, heart chambers, and CNS have all been cloned first in model systems (1, 2, 21, 26, 28, 30, 32, 33) and then studied in mammals as well as humans. Genes responsible for programmed cell death were first cloned in C. elegans (27), and their homologues were found afterward in mammals and humans. The whole field of molecular physiology and, in particular, ion channels received a major boost after the cloning of the K+ channel from the fruit fly (10, 13). Very recently, Wingrove and O'Farrell (34) have also shown that the nitric oxide pathway is conserved in flies and humans in O2 sensing.
There are a number of reasons for the success of these genetic models in understanding normal biology. One major reason is that they enjoy important advantages, some conceptual and others technical. Although the space allocated for this mini-review does not allow detailing these advantages, I will briefly mention a few that have been particularly helpful in work done in Drosophila. 1) The Drosophila has a number of useful characteristics of a genetic model: a small number of chromosomes, a generation time of 10 days at 25°C, and a generation size of more than 200-300 per female. 2) There is an enormous number of mutant lines (deficiencies, inversions, P elements, and so forth) and chromosomal markers available for use. 3) Molecular tools such as libraries are available. 4) There are tools available for the study of cell or organ physiology in Drosophila (see below). Finally, 5) P elements, which are transposable DNA elements with known sequences, have been very useful in Drosophila for cloning and mapping purposes.
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SPECIFIC QUESTIONS AND APPROACHES IN DROSOPHILA |
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Our long-standing interest has been in the area of cell and tissue hypoxia. More specifically, we have been very interested in the response of cells, in particular nerve cells, to O2 deprivation and in nerve cell injury. If this is our interest, how does a genetic model such as Drosophila help us? Because Drosophila survives long periods of anoxia, we took advantage of this situation and specifically asked what is the Drosophila endowed with genetically to be able to resist anoxia for many hours?
To answer this question, a number of approaches can be used. We have used three of these possible approaches in parallel and have obtained very interesting results. Below is a brief outline of each approach and a summary of the results obtained.
A genetic approach. Assuming that there are genes in the Drosophila that protect cells and tissues from anoxic injury, the main idea here is to mutagenize the fly genome and develop a mutagenesis screen to identify flies that have lost these genes, i.e., flies that have loss-of-function mutations. Then, these mutations are mapped in detail using marker chromosomes and small deficiencies and then cloned. The genes responsible for the abnormal phenotype are then ascertained in various ways, including the use of transgenic techniques and rescue experiments. This approach has two main advantages: 1) we start with a phenotype that is useful and that is relevant to the question asked, and 2) there is no bias in terms of the genes and molecules found; whatever genes are found in the mutagenesis screen are studied.
Although we had no a priori reason to suspect that the genes of interest are exclusively located on the X chromosome, we focused our screen for mutations on that chromosome for two reasons. The first is to limit our initial task, but the main reason is strategic. An advantage of focussing on the X chromosome is that, using a specific cross, the screening for mutations on the X chromosome for a specific phenotype can be observed in the immediate next generation without the need for subsequent single-pair matings. Thus we will be able to screen for recessive mutations in the immediate next generation, since the investigation is done in males. There are at least three ways for mutagenizing the genome in the Drosophila: 1) X-rays, 2) ethylmethane sulfonate, and 3) P element insertional mutagenesis. There are advantages and disadvantages for each of these methods, but space in this mini-review does not allow us to detail these. We have started with X-ray mutagenesis and P elements, but most of our results so far are obtained from X-ray mutagenesis. We therefore mutagenized (X-ray, 4,000 rad) C-S or wild-type males and crossed them to attached X females [c(1)ywf]. By doing this, irradiated males (and hence carrying mutations on all three chromosomes) will transmit their mutated X chromosome to the male offspring (which is different from the usual situation in which the male offspring inherits the X chromosome from the female parent). Therefore, by testing the first generation male progeny, we could test for mutations, irrespective of whether the mutations are recessive or dominant, since, like humans and mammals, male flies have one X chromosome. In a specialized apparatus, more than 22,000 flies, carrying mutagenized chromosomes, have been screened so far in our laboratory (13). Because we had already studied in detail the wild-type responses and developed distribution profiles (histograms) about the recovery from anoxia (13), a threshold (close to the 96th percentile of the wild-type distribution) was used to identify and isolate mutants. To date, we have identified 10 mutants that have loss-of-function mutations and 8 complementation groups (2 mutations have 2 weaker alleles isolated as well), and the mutants have profoundly altered distribution of recovery times after reoxygenation. The marked delay in recovery after anoxia displayed by these mutant flies suggested to us that they were much more sensitive to lack of O2 (13, 19) (Fig. 1).
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Differential display and reverse genetics. The idea behind this approach is to identify those genes that are differentially expressed during a condition or a stress. In our case, we use very low levels of O2 and assess whether there are mRNA that are up- or downregulated in naive or nonexposed organisms in comparison to exposed (anoxia-exposed) Drosophila. RNA differential display was performed as previously described by Liang and Pardee (22), with minor modifications. Although there are several differences between this approach and the first one, it is clear that the main difference is that this approach starts with a gene (reverse genetics), whereas the first starts with a phenotype (genetics). Hence, in this second approach, the proof that a particular gene is relevant to the phenomenon of interest would have to await additional investigations beyond the differential display such as transgenic studies as we have done (see below).
The data from our differential display clearly showed that certain genes were upregulated, whereas others were downregulated, during anoxia (23, 24). From the PCR reactions, we found that the expression level of several transcripts was visibly affected by anoxia. We have selected one transcript, which was markedly upregulated, to focus on and study. We termed this transcript fau (fly, anoxia, upregulated) (24). The fau cDNA and its deduced protein sequence have several interesting characteristics. For example, 1) several ATTT motifs were found in its 3'-UTR. These motifs, reportedly, play a role in the stability of transient mRNAs (24) and may therefore play a similar role in hypoxia-induced mRNAs and could regulate their expression (24). In addition, there are two (TA)9-10 stretches in the 3'-UTR of this cDNA. Although their function is not clear, together, these unique sequences in the 3'-UTR with high GC content in the fau cDNA open reading frame may define a functional anatomy important in the transient or stress-induced mRNAs. 2) The deduced protein sequence of fau cDNA also has a high number of phosphorylation sites, which makes it an appropriate substrate for phosphorylation. It is possible then that the fau protein can participate in transient pathways that depend on phosphorylation or dephosphorylation. Because our computerized search did not reveal a significant homology with published sequences, the deduced fau protein is most likely a novel phosphorylated one (Fig. 3).
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Known gene products in mammalian cells and tissues. Another approach is to clone from Drosophila the genes that seem to be important in mammals. This would allow the study of gene networks and therefore the study of the genes that modify the expression or the function of particular genes of interest. For example, we know now that the hypoxia-inducible factor 1 (HIF-1) plays an important role in mammals in hypoxia and development. To study the genetic network that HIF-1 is involved in mammals is rather difficult, especially when one considers in vivo experiments. However, this is possible in Drosophila. Therefore, this is first studied in the fly (22, 23), and then the genes discovered in the fly are looked for in mammals. The use of Drosophila would likely be useful, since it would be much easier to investigate modifier genes and their pathways in a well-studied genetic model rather than in mammals. We have also adopted such a method and have done some work in this area, as illustrated in our previous publications (22, 23).
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FUTURE DIRECTIONS: IS DROSOPHILA RESEARCH A "DETOUR" OR A "SHORTCUT"? |
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From our work to date on Drosophila, we conclude that there are specific individual genes in the Drosophila genome that are protective against hypoxic injury and that their mutations lead to cellular injury. Furthermore, these studies have taught us that it is possible to start to dissect the genetic nature of anoxia tolerance in tolerant organisms, a phenomenon that has so far been elusive at best. We also conclude that future experiments in our mutagenesis work should include 1) refining the mutational maps of the loci of interest, 2) building further alleles of the mutations that we have already isolated, 3) characterizing further the phenotype of our loss-of-function mutants and extending the mutagenesis screen to the analysis of the autosomes, 4) expanding the mutagenesis screen to include insertional mutagenesis with P elements, 5) cloning the various mutations and studying the epistatic relationships between them, and, finally, 6) studying the cell biology and physiology of these genes. In addition, we conclude that reverse genetics work should include 1) performing additional differential display reactions to examine all or near all of the fly genome, 2) studying their tissue expression as well as their chromosomal localizations, 3) constructing transgenic flies carrying the mutant gene or an overexpressed gene to study its impact on whole animal function, and 4) finding homologues of the Drosophila genes in mammals.
So far, when the work done on Drosophila and other genetic models, including the C. elegans and the zebrafish, over the past two decades is critically evaluated, it becomes clear that these models have enhanced our understanding of normal biological processes and disease conditions not only in these model systems but also in mammals and in humans. Furthermore, with the completion of the genome project in yeast and C. elegans and soon with the completion of the genome project of the fly and shortly in humans, the pace at which we will uncover molecular mechanisms and how genes function will increase, and the best is yet to come! The current consensus is that the work in Drosophila is a shortcut that will enhance, at a faster pace, our understanding of the molecular basis of biology and disease states in humans.
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FOOTNOTES |
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Second in a series of invited mini-reviews on "Hypoxia Influence on Gene Expression."
Address for reprint requests and other correspondence: G. G. Haddad, Dept. of Pediatrics, Section of Respiratory Medicine, 333 Cedar St., FMP 506, New Haven, CT 06520 (E-mail: gabriel.haddad{at}yale.edu).
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B. S. Wu, J. K. Lee, K. M. Thompson, V. K. Walker, C. D. Moyes, and R. M. Robertson Anoxia induces thermotolerance in the locust flight system J. Exp. Biol., March 15, 2002; 205(6): 815 - 827. [Abstract] [Full Text] [PDF]
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Q. Chen, E. Ma, K. L. Behar, T. Xu, and G. G. Haddad Role of Trehalose Phosphate Synthase in Anoxia Tolerance and Development in Drosophila melanogaster J. Biol. Chem., January 25, 2002; 277(5): 3274 - 3279. [Abstract] [Full Text] [PDF]
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 R.J. ROMAN, A.W. COWLEY, A. GREENE, A.E. KWITEK, P.J. TONELLATO, and H.J. JACOB Consomic Rats for the Identification of Genes and Pathways Underlying Cardiovascular Disease Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 309 - 316. [Abstract] [PDF]
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