InteractiveFly: GeneBrief

Drop dead: Biological Overview | References

The eggshell of the fruit fly Drosophila melanogaster is a useful model for understanding the synthesis of a complex extracellular matrix. The eggshell is synthesized during mid-to-late oogenesis by the somatic follicle cells that surround the developing oocyte. Previous studies have shown that female flies mutant for the gene drop-dead (drd) are sterile, but the underlying cause of the sterility remained unknown. This study examined the role of drd in eggshell synthesis. Eggs laid by drd mutant females are fertilized but arrest early in embryogenesis, and the innermost layer of the eggshell, the vitelline membrane (VM), is abnormally permeable to dye in these eggs. In addition, the major vitelline membrane proteins fail to become crosslinked by nonreducible bonds, a process that normally occurs during egg activation following ovulation, as evidenced by their solubility and detection by Western blot in laid eggs. In contrast, the Cp36 protein, which is found in the outer chorion layers of the eggshell, becomes crosslinked normally. To link the drd expression pattern with these phenotypes,drd was shown to be expressed in the ovarian follicle cells beginning in mid-oogenesis, and, importantly, that all drd mutant eggshell phenotypes could be recapitulated by selective knockdown of drd expression in the follicle cells. To determine whether drd expression was required for the crosslinking itself, in vitro activation and crosslinking experiments were performed. The vitelline membranes of control egg chambers could become crosslinked either by incubation in hyperosmotic medium, which activates the egg chambers, or by exogenous peroxidase and hydrogen peroxide. In contrast, neither treatment resulted in the crosslinking of the vitelline membrane in drd mutant egg chambers. These results indicate that drd expression in the follicle cells is necessary for vitelline membrane proteins to serve as substrates for peroxidase-mediated cross-linking at the end of oogenesis (Sheahan, 2023).

Animal epithelial cells produce an extracellular matrix (ECM) that must perform many roles, including as a structural support, barrier, and source of signaling molecules. The eggshell of the insect Drosophila melanogaster is a model ECM consisting of five layers of protein, lipid, and carbohydrate. Among its functions, the Drosophila eggshell serves as physical protection and a selective permeability barrier, provides patterning signals for the oocyte and developing embryo, and binds pheromones that prevent cannibalism by conspecific larvae. Eggshell components are primarily synthesized by the follicle cells, a layer of somatic epithelial cells that surround the 15 germline nurse cells and single oocyte; together these three cell types make up the basic unit of oogenesis, the egg chamber (Sheahan, 2023).

Early in oogenesis, the follicle cells form a morphologically uniform, cuboidal epithelium around the germline cells, with the apical surface of the epithelium facing the germline. At mid-oogenesis (stage 8 of the 14 stages of oogenesis), the oocyte begins to grow, and the large majority of follicle cells subsequently migrate posteriorly to cover the oocyte surface and undergo a transition from cuboidal to columnar morphology. A small number of follicle cells, the stretch cells, remain covering the nurse cells and transition to a squamous morphology; the stretch cells are required for the death and engulfment of the nurse cells in late oogenesis. At the end of oogenesis (stage 14), the oocyte takes up the entire egg chamber, the follicle cells undergo cell death, and the follicle cell layer is shed during ovulation (Sheahan, 2023).

The innermost layer of the eggshell is the proteinaceous vitelline membrane (VM). It is composed of six related structural proteins encoded by the genes Vm26Aa, Vm26Ab, Vm26Ac, Vm32E, Vm34Ca, and Vml, as well as other less abundant proteins. While most VM components are produced by the follicle cells and secreted apically, at least three proteins, encoded by fs(1)Nasrat (fs(1)N), fs(1)polehole (fs(1)ph) and closca (clos), are secreted by the oocyte and become incorporated into the developing VM. VM components are synthesized during mid-oogenesis, followed by components of the multilayered outer sections of the eggshell, the chorion, in stages 11–12 (Sheahan, 2023).

Following their synthesis and secretion, the proteins of the VM become cross-linked, forming a stable and insoluble matrix. The VM proteins are cross-linked to each other by disulfide bonds during the early stages of eggshell formation. Immediately following ovulation and egg activation, VM proteins become cross-linked by non-reducible bonds, at least some of which are dityrosine bonds. The non-reducible cross-linking of the VM occurs in a matter of minutes as the egg moves down the oviduct; soluble VM proteins are never detected in freshly laid eggs. While the formation of dityrosine bonds is typically catalyzed by a peroxidase, the enzyme responsible for VM crosslinking has not been identified (Sheahan, 2023).

The structural integrity of the Drosophila VM can be disrupted by mutations in several genes. Mutation of many of the genes encoding VM structural proteins causes gross VM abnormalities and collapse of the eggs, as do mutations in the cadherin Cad99C which is localized to microvilli on the apical surface of the follicle cells, and the eggshell components yellow-g and yellow-g2. Other mutations, in the genes encoding the minor eggshell components Nudel, Palisade (Psd), Clos, Fs(1)ph, and Fs(1)N, result in a disruption in VM protein cross-linking without altering overall VM integrity to the extent of causing eggs to collapse, however all of these mutations result in female sterility (Sheahan, 2023).

In this paper, the role was studied of the drop-dead (drd) gene in oogenesis. drd encodes a putative integral membrane protein of unknown function with homology to prokaryotic acyltransferases. Mutation of drd causes a wide range of phenotypes, including female sterility, early adult death and neurodegeneration, defective food movement through the gut, and absence of a peritrophic matrix from the midgut. The basis for female sterility has not previously been reported. This study demonstrates that drd expression in the follicle cells is required for non-reducible cross-linking of the VM (Sheahan, 2023).

Expression of drd in the ovarian follicle cells was found to be both necessary and sufficient for female fertility and the progression of embryonic development beyond gastrulation. drd is expressed in ovarian follicle cells, but not the germline. A reporter that is expected to mimic the pattern of drd expression was expressed in the ovarian follicle cells and not the germline. Consistent with this, the result of a dominant female sterile experiment indicates that drd expression in the female germline is not required for fertility, while knockdown of drd expression specifically in the follicle cells recapitulates the mutant phenotype. These results are in keeping with those of Kim (2012) who reported expression of drd in the follicle cells. Furthermore, it was shown that drd expression in the follicle cells is required for proper development of the VM layer of the eggshell. In the absence of such expression, many eggs collapse, and the remaining eggs have a fragile VM that fails to act as a permeability barrier. Several major VM proteins—specifically those recognized by the antibody used in these studies—remain soluble in the presence of reducing agents, indicating that they have not been incorporated into the insoluble network of cross-linked proteins seen in the wild-type VM. The variable solubility phenotype observed with knockdown of drd with the T155-GAL4 driver is consistent with the fertility of some of these drd knockdown females and suggests that T155-GAL4 is not as effective as the CY2-GAL4 driver in knocking down drd expression. The difference in strength of these two driver lines has been reported previously (Sheahan, 2023).

The solubility of VM proteins in eggs laid by drd mutants indicates a defect in the peroxidase-mediated cross-linking that normally occurs upon egg activation while the egg is transiting down the oviduct. There is no evidence that egg activation itself is defective, as the eggs were able to complete the early stages of embryogenesis. The data in this study don’t address the connection between defective VM cross-linking and embryonic arrest. Although it is possible that embryonic arrest is a drd phenotype independent of the defect in VM cross-linking, it has previously been reported that defective VM cross-linking is sufficient to cause early embryonic arrest. Females mutant for psd, which encodes a minor VM protein, also lay eggs with a VM cross-linking defect and that arrest pre-gastrulation and show a chromatin margination phenotype similar to that induced by anoxia. Similarly, females with class I alleles of the eggshell component nudel lay eggs that exhibit VM cross-linking defects and, though extremely fragile, are fertilized and arrest early in embryogenesis. Thus, it is likely that defective VM cross-linking is also the direct cause of early developmental arrest in drd mutants. While this study did not find a role for drd in embryonic development, based on current experiments, such a role cannot be ruled out (Sheahan, 2023).

A published microarray study of ovarian gene expression has reported that drd expression in the egg chamber begins at stage 8 of oogenesis, peaks at stages 10A and 10B, and then declines. The timing of drd expression therefore parallels the synthesis and secretion of VM proteins by the follicle cells. The pattern of reporter expression is consistent with the microarray data. GFP fluorescence was observed starting at stage 10B and persisting through the rest of oogenesis; one would expect both a delay between the onset of GFP expression and significant accumulation in the follicle cell nuclei and persistence of the protein after gene expression is downregulated. The drd protein is unlikely to be a component of the VM, as it is predicted to be an integral membrane protein and is reported to be localized to an intracellular compartment. drd is also unlikely to be directly involved in the cross-linking process, which occurs at the end of oogenesis when drd expression is very low. Rather, the data suggest that the failure of VM proteins to become cross-linked in drd mutants could be due to an absence of some modification of the VM proteins in the follicle cells prior to secretion. The results of a final experiment are consistent with this hypothesis. Incubation of stage 14 egg chambers with peroxide and peroxidase resulted in cross-linking of the VM in egg chambers from wild-type but not drd mutant females. Thus, VM proteins synthesized and secreted from drd mutant follicle cells appear to be poor substrates for peroxidase-mediated cross-linking for reasons still to be determined (Sheahan, 2023).

One interesting finding from a final experiment is that egg chambers from drd mutant females dissolve immediately in bleach after activation in vitro with hypo-osmotic medium. In contrast, eggs laid by drd mutant females mainly survive bleaching, even though their VMs are permeable to neutral red. The contrast between these two results indicates that hypo-osmotic treatment in vitro does not fully recapitulate the activation process in vivo even though the two processes appear to give identical results in wild-type flies. Additional study of oogenesis in drd mutant females could prove to be useful for identifying additional factors required for eggshell maturation during ovulation (Sheahan, 2023).

In addition to characterizing the effect of drd mutations on oogenesis, this study haa identified the molecular defect in the severe drd 1 allele as a point mutation in the final intron that disrupts the normal splicing of exons 8 and 9. The aberrant splicing replaces the final 76 residues of the 827 amino acid drd protein with a novel sequence. drd1 has previously been shown to cause the same short adult lifespan, female sterility, and absence of a peritrophic matrix as drd^lwf, a nonsense mutation that eliminates all but the first 180 amino acids. Thus, this finding highlights the importance of the C-terminal of drd in protein function, stability, or localization. In contrast, the drd^W3 and In(1)drdx1 alleles, which eliminate the first exon and at least the first 125 amino acids, are phenotypically less severe (Sheahan, 2023).

The biochemical function of the drd protein remains unknown. However, this study highlights two themes that are emerging from studies of this gene. First, drd expression appears to be required in a number of different epithelial tissues, including the ovarian follicle cells for oogenesis, the anterior midgut for digestive function, and the respiratory tracheae for brain integrity. Second, drd expression is required for the formation of extracellular barrier structures, as drd mutants show defects both in the eggshell and in the peritrophic matrix of the midgut. Given the amount of information known about eggshell formation, the ovary is an excellent system for further studies of drd function (Sheahan, 2023).

Pleiotropic and novel phenotypes in the Drosophila gut caused by mutation of drop-dead

Normal gut function is vital for animal survival. In Drosophila, mutation of the gene drop-dead results in defective gut function, as measured by enlargement of the crop and reduced food movement through the gut, and drd mutation also causes the unrelated phenotypes of neurodegeneration, early adult lethality and female sterility. This work shows that adult drd mutant flies lack the peritrophic matrix (PM), an extracellular barrier that lines the lumen of the midgut and is found in many insects including flies, mosquitos and termites. The use of a drd-gal4 construct to drive a GFP reporter in late pupae and adults revealed drd expression in the anterior cardia, the site of PM synthesis in Drosophila and a valve and regulates the passage of food into the anterior midgut and crop. Moreover, the ability of drd knockdown or rescue with several gal4 drivers to recapitulate or rescue the gut phenotypes (lack of a PM, reduced defecation, and reduced adult survival 10-40 days post-eclosion) was correlated to the level of expression of each driver in the anterior cardia. Surprisingly, however, knocking down drd expression only in adult flies, which has previously been shown not to affect survival, eliminated the PM without reducing defecation rate. These results demonstrate that drd mutant flies have a novel phenotype, the absence of a PM, which is functionally separable from the previously described gut dysfunction observed in these flies. As the first mutant Drosophila strain reported to lack a PM, drd mutants will be a useful tool for studying the synthesis of this structure (Conway, 2018).

This study reports a novel and unique gut phenotype of drd mutants: the absence of a PM. To be more precise, adult drd lack a detectable PM by gross dissection, chitin staining, and histology, while the PM is still present in larval drd mutants. However, the Drosophila PM has been shown to consist of at least four distinct layers, not all of which might contain chitin. It is possible that drd mutants lack only the first layer, and that the material that would normally make up the remaining layers either fails to condense into a discrete structure or forms a structure that is not detectable by either histology or gross dissection. Consistent with a specific effect on a single chitinous layer of the PM, drd expression in the cardia appears to be localized to a region just anterior to the foregut/midgut transition, termed zones 2 and 3, which is where the first layer of the PM is synthesized (Conway, 2018).

The DRD protein is proposed to function as an acyltransferase, based on sequence homology to biochemically characterized prokaryotic proteins, but no biochemical function for DRD or any related eukaryotic protein has been reported. The protein contains multiple putative membrane-spanning domains and has been localized to an unidentified intracellular compartment. Based on its location and structure, it is possible that DRD is required in the secretory pathway of cardia epithelial cells for the posttranslational modification of a PM structural protein or synthetic enzyme (Conway, 2018).

In a previous study, tracheal-specific knockdown and rescue of drd expression was used to identify the suite of phenotypes associated with a lack of drd expression in the tracheae, namely early adult lethality and neurodegeneration but not gut dysfunction. The current work shows that expression of drd in the pattern defined by the DJ626 driver, which is expressed in both the tracheae and the anterior cardia, was both necessary and sufficient for both the "tracheal" phenotypes of early lethality and neurodegeneration and the "gut" phenotypes of reduced defecation and the absence of a PM. The pattern defined by the DJ717 driver, which is expressed at lower levels in the cardia than DJ626 and is also expressed in the tracheae, was both necessary and sufficient for the tracheal phenotypes and was effective in creating the gut phenotypes in knockdown experiments but not in rescuing them. These data suggest that the gut phenotypes are related to drd expression in the cardia. However, both DJ626 and DJ717 are expressed in other tissues and other parts of the gut, and the absence of a driver specific to the anterior cardia precludes a direct test of this hypothesis (Conway, 2018).

Using temporal control of drd expression, it is possible to separate the two gut phenotypes, with the presence of a PM associated with drd expression in the adult and normal defecation associated with drd expression during pre-adult development. This result was surprising in two respects. First, it shows that the presence of the PM is not required for movement of ingested food through the fly’s digestive tract. Second, it demonstrates that drd plays at least two different roles in the development and maintenance of the Drosophila gut and that the roles occur during different stages of the organism’s life cycle. As further evidence for the pleiotropic nature of drd function, this study found that rescuing drd expression with the DJ626 driver did not fully rescue adult lethality, while rescuing expression with the drd-gal4 driver did achieve a complete rescue in survival. Thus, it appears that besides neurodegeneration and reduced food movement through the gut, drd mutants have at least one more physiological defect that eventually leads to adult lethality. The drd -gal4 driver will be an important tool in identifying further drd phenotypes by revealing the full expression pattern of drd (Conway, 2018).

By knocking down drd expression only during adulthood, it is possible to create flies that lack a PM, and this treatment has no effect on adult survival. However, in order to sustain drd knockdown in the adult, it is necessary to maintain flies at 30 °C. Under these conditions, both knockdown and control flies began dying around 15 days post eclosion and exhibited 100% mortality by day 40. It has been reported that flies mutant for the PM protein Crystallin (DCY), which have a leaky PM, begin dying around day 20 after eclosion and show approximately 50% mortality by day 40 (Kuraish. Due to the temperature-induced lethality observed in adult knockdown flies, the possibility that the PM is required for adult survival beyond three weeks cannot be excluded, consistent with the results of Kuraishi et al (Conway, 2018).

It has previously been reported that a "PM-less" phenotype can be created in the larvae of several insect species through feeding with either Calcofluor or chitinase. However, the drd mutant flies are the first reported Drosophila strain with a genetically ablated PM. Interest in the adult insect PM has increased recently due to its theorized role in immunity, microbiome maintenance, and virulence propagation and its identity as a potential target for pesticides. Studying gut function in drd mutants and knockdowns is complicated by the expression and function of drd in multiple tissues and the many severe phenotypes that are independent of the PM. However, this mutation causes a more complete phenotype than "leaky" PM models, and the drd mutant fly is anticipated to be an invaluable tool to better study the physiological roles and developmental pathways leading to the synthesis of the PM (Conway, 2018).

Neurodegeneration in drop-dead mutant drosophila melanogaster is associated with the respiratory system but not with Hypoxiae

Mutations in the gene drop-dead (drd ) cause diverse phenotypes in adult Drosophila melanogaster including early lethality, neurodegeneration, tracheal defects, gut dysfunction, reduced body mass, and female sterility. Despite the identification of the drd gene itself, the causes of early lethality and neurodegeneration in the mutant flies remain unknown. To determine the pattern of drd expression associated with the neurodegenerative phenotype, knockdown of drd with various Gal4 drivers was performed. Early adult lethality and neurodegeneration were observed upon knockdown of drd in the tracheal system with two independent insertions of the breathless-Gal4 driver and upon knockdown in the tracheal system and elsewhere with the DJ717-Gal4 driver. Surprisingly, rescue of drd expression exclusively in the tracheae in otherwise mutant flies rescued the neurodegenerative phenotype but not adult lethality. Gut dysfunction, as measured by defecation rate, was not rescued in these flies, and gut function appeared normal upon tracheal-specific knockdown of . Finally, the hypothesis that tracheal dysfunction in mutants results in hypoxia was tested. Hypoxia-sensitive reporter transgenes (LDH-Gal4 and LDH-LacZ) were placed on a mutant background, but enhanced expression of these reporters was not observed. In addition, manipulation of expression in the tracheae did not affect expression of the hypoxia-induced genes LDH, tango, and similar. Overall, these results indicate that there are at least two causes of adult lethality in mutants, that gut dysfunction and neurodegeneration are independent phenotypes, and that neurodegeneration is associated with tracheal expression of but not with hypoxia (Sansone, 2013).

Developmental expression of drop-dead is required for early adult survival and normal body mass in Drosophila melanogaster

In Drosophila melanogaster, mutations in the gene drop-dead (drd) result in early adult lethality, with flies dying within 2 weeks of eclosion. Additional phenotypes include neurodegeneration, tracheal defects, starvation, reduced body mass, and female sterility. The cause of early lethality and the function of the drd protein remain unknown. In the current study, the temporal profiles of drd expression required for adult survival and body mass regulation were investigated. Knockdown of drd expression by UAS-RNAi transgenes and rescue of drd expression on a drd mutant background by a UAS-drd transgene were controlled with the Heat Shock Protein 70 (Hsp70)-Gal4 driver. Flies were heat-shocked at different stages of their lifecycle, and the survival and body mass of the resulting adult flies were assayed. Surprisingly, the adult lethal phenotype did not depend upon drd expression in the adult. Rather, expression of drd during the second half of metamorphosis was both necessary and sufficient to prevent rapid adult mortality. In contrast, the attainment of normal adult body mass required a different temporal pattern of drd expression. In this case, manipulation of drd expression solely during larval development or metamorphosis had no effect on body mass, while knockdown or rescue of drd expression during all of pre-adult (embryonic, larval, and pupal) development did significantly alter body mass. Together, these results indicate that the adult-lethal gene drd is required only during development. Furthermore, the mutant phenotypes of body mass and lifespan are separable phenotypes arising from an absence of drd expression at different developmental stages (Sansone, 2012).

Drosophila drop-dead mutants is associated with hypoxia in the brain

The Drosophila drop-dead (drd) mutant undergoes massive brain degeneration, resulting in sudden death. drd encodes a multi-pass membrane protein possessing nose resistant to fluoxetine (NRF) and putative acyltransferase domains. However, the etiology of brain degeneration that occurs in drd mutant flies is still poorly understood. This study shows that drd neurodegeneration may be because of an oxygen deficit in the brain. drd protein is selectively expressed in cells secreting cuticular and eggshell layers. These layers exhibit blue fluorescence upon UV excitation, which is reduced in drd flies. The drd tracheal air sacs lacking blue fluorescence collapse, which likely contributes to hypoxia. Consistently, genes induced in hypoxia are up-regulated in drd flies. Feeding of anti-reactive oxygen species agents partially rescue the drd from sudden death. drd flies are proposed to provide a non-invasive animal model for hypoxia-induced cell death (Kim, 2012).

Cloning of the neurodegeneration gene drop-dead and characterization of additional phenotypes of its mutation

Mutations in the Drosophila gene drop-dead (drd) result in early adult lethality and neurodegeneration, but the molecular identity of the drd gene and its mechanism of action are not known. This paper describes the characterization of a new X-linked recessive adult-lethal mutation, originally called lot's wife (lwf¹) but subsequently identified as an allele of drd (drd(^lwf); drd(^lwf)) mutants die within two weeks of eclosion. Through mapping and complementation, the drd gene has been identified as CG33968, which encodes a putative integral membrane protein of unknown function. The drd^lwf allele is associated with a nonsense mutation that eliminates nearly 80% of the CG33968 gene product; mutations in the same gene were also found in two previously described drd alleles. Characterization of drd^lwf) flies revealed additional phenotypes of drd, most notably, defects in food processing by the digestive system and in oogenesis. Mutant flies store significantly more food in their crops and defecate less than wild-type flies, suggesting that normal transfer of ingested food from the crop into the midgut is dependent upon the drd gene product. The defect in oogenesis results in the sterility of homozygous mutant females and is associated with a reduction in the number of vitellogenic egg chambers. The disruption in vitellogenesis is far more severe than that seen in starved flies and so is unlikely to be a secondary consequence of the digestive phenotype. This study demonstrates that mutation of the drd gene results in a complex phenotype affecting multiple physiological systems within the fly (Blumenthal, 2008).

Locomotor performance in the Drosophila brain mutant drop-dead

Mutation of the drop-dead gene in Drosophila causes early death of the adult animal. After hatching from pupae, drop-dead mutants increasingly lose body control and typically die within ten days. Drop-dead carries an X-chromosomal recessive mutation that causes brain degeneration, due to a loss in glia function. Recent results attribute this functional deficiency to a component required to form the tracheolar respiratory apparatus and thus to a reduction of tracheal oxygen supply. If the reduction of respiratory capacity is the primary reason for brain degeneration, locomotor capacity of drop-dead should be significantly impaired. Running performance and locomotor motivation of drop-dead¹ mutants were determined at ages between one and five days. The mutant achieves similar mean and maximum forward speeds during running of approximately 1.5 and 10 mms^-1, respectively, as wild type flies. Thus metabolic capacity required for running seems not to be compromised. drop-dead¹ flies, however, are significantly more active (34%) and also have a higher motivation (33%) to initiate running. Heading instability during forward running was increased by 17% compared to wild type and tended to increase with age. These findings are consistent with the previously reported loss in body control in the mutant and thus demonstrate the significance of the drop-dead¹ gene for running behaviour in Drosophila (Lehmann, 2010).

Defective gut function in drop-dead mutant Drosophila

Mutation of the gene drop-dead (drd) causes adult Drosophila to die within 2 weeks of eclosion and is associated with reduced rates of defecation and increased volumes of crop contents. This study demonstrates that flies carrying the strong allele drd(lwf) display a reduction in the transfer of ingested food from the crop to the midgut, as measured both as a change in the steady-state distribution of food within the gut and also in the rates of crop emptying and midgut filling following a single meal. Mutant flies have abnormal triglyceride (TG) and glycogen stores over the first 4 days post-eclosion, consistent with their inability to move food into the midgut for digestion and nutrient absorption. However, the lifespan of mutants was dependent upon food presence and quality, suggesting that at least some individual flies were able to digest some food. Finally, spontaneous motility of the crop was abnormal in drd(^lwf) flies, with the crops of mutant flies contracting significantly more rapidly than those of heterozygous controls. It is therefore hypothesized that mutation of drd causes a structural or regulatory defect that inhibits the entry of food into the midgut (Peller, 2009).

Drosophila rop-dead mutations accelerate the time course of age-related markers

Mutations of the drop-dead gene in Drosophila melanogaster lead to striking early death of the adult animal. At different times, after emergence from the pupa, individual flies begin to stagger and, shortly thereafter, die. Anatomical examination reveals gross neuropathological lesions in the brain. The life span of flies mutant for the drop-dead gene is four to five times shorter than for normal adults. That raises the question whether loss of the normal gene product might set into motion a series of events typical of the normal aging process. Molecular markers were used, the expression patterns of which, in normal flies, change with age in a manner that correlates with life span. In the drop-dead mutant, there is an acceleration in the temporal pattern of expression of these age-related markers (Rogina, 1997).

Defective glia in the Drosophila brain degeneration mutant drop-dead

To understand better the cellular basis of late-onset neuronal degeneration, this study has examined the brain of the drop-dead mutant of Drosophila. This mutant carries an X-chromosomal recessive mutation that causes severe behavioral defects and brain degeneration, manifested a few days after emergence of the adult. Analysis of genetically mosaic flies has indicated that the focus of the drop-dead mutant phenotype is in the brain and that the gene product is non-cell autonomous. The adult drop-dead mutant brain was examined prior to onset of symptoms; many glial cells have stunted processes, whereas neuronal morphology is essentially normal. Adult mutant glial cells resemble immature glia found at an earlier stage of normal brain development. These observations suggest that defective glia in the drop-dead brain may disrupt adult nervous system function, contributing to progressive brain degeneration and death. The normal drop-dead gene product may prevent brain degeneration by providing a necessary glial function.

Search PubMed for articles about Drosophila Drop dead

Buchanan, R. L., Benzer, S. (1993). Defective glia in the Drosophila brain degeneration mutant drop-dead. Neuron, 10(5):839-850 PubMed ID: 8494644

Blumenthal, E. M. (2008). Cloning of the neurodegeneration gene drop-dead and characterization of additional phenotypes of its mutation. Fly (Austin), 2(4):180-188 PubMed ID: 18719404

Conway, S., Sansone, C. L., Benske, A., Kentala, K., Billen, J., Broeck, J. V. and Blumenthal, E. M. (2018). Pleiotropic and novel phenotypes in the Drosophila gut caused by mutation of drop-dead. J Insect Physiol. PubMed ID: 29371099

Kim, J. Y., Jang, W., Lee, H. W., Park, E., Kim, C. (2012). Neurodegeneration of Drosophila drop-dead mutants is associated with hypoxia in the brain. Genes Brain Behav, 11(2):177-184 PubMed ID: 22010830

Lehmann, F. O., Cierotzki, V. (2010). Locomotor performance in the Drosophila brain mutant drop-dead. Comp Biochem Physiol A Mol Integr Physiol, 156(3):337-343 PubMed ID: 20045484

Peller, C. R., Bacon, E. M., Bucheger, J. A., Blumenthal, E. M. (2009). Defective gut function in drop-dead mutant Drosophila. J Insect Physiol, 55(9):834-839 PubMed ID: 19500585

Rogina, B., Benzer, S., Helfand, S. L. (1997). Drosophila drop-dead mutations accelerate the time course of age-related markers. Proc Natl Acad Sci U S A, 94(12):6303-6306 PubMed ID: 9177212

Sansone, C. L., Blumenthal, E. M. (2012). Developmental expression of drop-dead is required for early adult survival and normal body mass in Drosophila melanogaster. Insect Biochem Mol Biol, 42(9):690-698 PubMed ID: 22728457

Sheahan, T. D., Grewal, A., Korthauer, L. E., Blumenthal, E. M. (2023).The Drosophila drop-dead gene is required for eggshell integrity. PLoS One, 18(12):e0295412 PubMed ID: 38051756

date revised: 5 April 2025

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