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Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset neurodegenerative disease characterized by the progressive degeneration of upper and lower motoneurons. Most ALS cases are sporadic but approximately 10% of ALS cases are due to inherited mutations in identified genes. ALS-causing mutations were identified in over 30 genes with superoxide dismutase-1 (SOD1), chromosome 9 open reading frame 72 (C9orf72), fused in sarcoma (FUS), and TAR DNA-binding protein (TARDBP, encoding TDP-43) being the most frequent. In the last few decades, Drosophila melanogaster emerged as a versatile model for studying neurodegenerative diseases, including ALS. In this review, we describe the different Drosophila ALS models that have been successfully used to decipher the cellular and molecular pathways associated with SOD1, C9orf72, FUS, and TDP-43. The study of the known fruit fly orthologs of these ALS-related genes yielded significant insights into cellular mechanisms and physiological functions. Moreover, genetic screening in tissue-specific gain-of-function mutants that mimic ALS-associated phenotypes identified disease-modifying genes. Here, we propose a comprehensive review on the Drosophila research focused on four ALS-linked genes that has revealed novel pathogenic mechanisms and identified potential therapeutic targets for future therapy.

One way to better understand the molecular mechanisms involved in the construction of a nervous system is to identify the downstream effectors of major regulatory proteins. We previously showed that Engrailed (EN) and Gooseberry-Neuro (GsbN) transcription factors act in partnership to drive the formation of posterior commissures in the central nervous system of Drosophila. In this report, we identified genes regulated by both EN and GsbN through chromatin immunoprecipitation ("ChIP on chip") and transcriptome experiments, combined to a genetic screen relied to the gene dose titration method. The genomic-scale approaches allowed us to define 175 potential targets of EN-GsbN regulation. We chose a subset of these genes to examine ventral nerve cord (VNC) defects and found that half of the mutated targets show clear VNC phenotypes when doubly heterozygous with en or gsbn mutations, or when homozygous. This strategy revealed new groups of genes never described for their implication in the construction of the nerve cord. Their identification suggests that, to construct the nerve cord, EN-GsbN may act at three levels, in: (i) sequential control of the attractive-repulsive signaling that ensures contralateral projection of the commissural axons, (ii) temporal control of the translation of some mRNAs, (iii) regulation of the capability of glial cells to act as commissural guideposts for developing axons. These results illustrate how an early, coordinated transcriptional control may orchestrate the various mechanisms involved in the formation of stereotyped neuronal networks. They also validate the overall strategy to identify genes that play crucial role in axonal pathfinding.

International audience; In many metazoans, final adult size depends on the growth rate and the duration of the growth period, two parameters influenced by nutritional cues. We demonstrate that, in Drosophila, nutrition modifies the timing of development by acting on the prothoracic gland (PG), which secretes the molting hormone ecdysone. When activity of the Target of Rapamycin (TOR), a core component of the nutrient-responsive pathway, is reduced in the PG, the ecdysone peak that marks the end of larval development is abrogated. This extends the duration of growth and increases animal size. Conversely, the developmental delay caused by nutritional restriction is reversed by activating TOR solely in PG cells. Finally, nutrition acts on the PG during a restricted time window near the end of larval development that coincides with the commitment to pupariation. In conclusion, the PG uses TOR signaling to couple nutritional input with ecdysone production and developmental timing.

Insulin signaling is a conserved feature in all metazoans. It evolved with the appearance of multicellularity, allowing primordial metazoans to respond to a greater diversity of environmental signals. The insulin signaling pathway is highly conserved in insects and particularly in Drosophila, where it has been extensively studied in recent years and shown to control metabolism, growth, reproduction, and longevity. Because misregulation of the insulin/IGF pathway in humans plays a role in many medical disorders, such as diabetes and various types of cancer, unraveling the regulation of insulin/IGF signaling using the power of a genetically tractable organism like Drosophila may contribute to the amelioration of these major human pathologies.

We identified the gene smooth (sm) in a screen for genes that are specifically expressed within the lineage that forms the adult chemosensory bristles. sm is expressed in most or all differentiating neurones during embryogenesis, but is specifically expressed in the neurones of the adult chemosensory organs on the wings and legs during metamorphosis. The inactivation of sm results in axonal defects in the chemosensory neurones, in the inability of mutant flies to feed and in their precocious death. As sm belongs to a family of heterogeneous nuclear ribonucleoprotein (hnRNP), we propose that the control of axonal navigation and connectivity is partly achieved at the level of mRNA splicing or exporting.

Summary: In Drosophila, the sensory organs are formed by cells that derive from a precursor cell through a fixed lineage. One exception to this rule is the bract cell that accompanies some of the adult bristles. The bract cell is derived from the surrounding epidermis and is induced by the bristle cells. On the adult tibia, bracts are associated with all mechanosensory bristles, but not with chemosensory bristles. The differences between chemosensory and mechanosensory lineages are controlled by the selector gene pox-neuro (poxn). Here we show that poxn is also involved in suppressing bract formation near the chemosensory bristles. We have identified the gene kek1, described as an inhibitor of the EGF-R signaling pathway, in a screen for poxn downstream genes. We show that kek1 can suppress bract formation and can interfere with other steps of sensory development, including SMC determination and shaft differentiation. genesis 39:246–255, 2004. © 2004 Wiley-Liss, Inc.

Background Huntington’s disease (HD) is caused by the abnormal expansion of the polyglutamine tract in the human Huntingtin protein (polyQ-hHtt). Although this mutation behaves dominantly, huntingtin loss of function also contributes to HD pathogenesis. Indeed, wild-type Huntingtin plays a protective role with respect to polyQ-hHtt induced defects. Methodology/Principal Findings The question that we addressed here is what part of the wild-type Huntingtin is responsible for these protective properties. We first screened peptides from the Huntingtin protein in HeLa cells and identified a 23 aa peptide (P42) that inhibits polyQ-hHtt aggregation. P42 is part of the endogenous Huntingtin protein and lies within a region rich in proteolytic sites that plays a critical role in the pathogenesis process. Using a Drosophila model of HD, we tested the protective properties of this peptide on aggregation, as well as on different polyQ-hHtt induced neuronal phenotypes: eye degeneration (an indicator of cell death), impairment of vesicular axonal trafficking, and physiological behaviors such as larval locomotion and adult survival. Together, our results demonstrate high protective properties for P42 in vivo, in whole animals. These data also demonstrate a specific role of P42 on Huntington’s disease model, since it has no effect on other models of polyQ-induced diseases, such as spinocerebellar ataxias. Conclusions/Significance Altogether our data show that P42, a 23 aa-long hHtt peptide, plays a protective role with respect to polyQ-hHtt aggregation as well as cellular and behavioral dysfunctions induced by polyQ-hHtt in vivo. Our study also confirms the correlation between polyQ-hHtt aggregation and neuronal defects. Finally, these results strongly suggest a therapeutic potential for P42, specific of Huntington’s disease.

All animals coordinate growth and maturation to reach their final size and shape. In insects, insulin family molecules control growth and metabolism, whereas pulses of the steroid 20-hydroxyecdysone (20E) initiate major developmental transitions. We show that 20E signaling also negatively controls animal growth rates by impeding general insulin signaling involving localization of the transcription factor dFOXO and transcription of the translation inhibitor 4E-BP . We also demonstrate that the larval fat body, equivalent to the vertebrate liver, is a key relay element for ecdysone-dependent growth inhibition. Hence, ecdysone counteracts the growth-promoting action of insulins, thus forming a humoral regulatory loop that determines organismal size.

We identified the gene smooth (sm) in a screen for genes that are specifically expressed within the lineage that forms the adult chemosensory bristles. sm is expressed in most or all differentiating neurones during embryogenesis, but is specifically expressed in the neurones of the adult chemosensory organs on the wings and legs during metamorphosis. The inactivation of sm results in axonal defects in the chemosensory neurones, in the inability of mutant flies to feed and in their precocious death. As sm belongs to a family of heterogeneous nuclear ribonucleoprotein (hnRNP), we propose that the control of axonal navigation and connectivity is partly achieved at the level of mRNA splicing or exporting.

Environmental cues affect the course of an organism's development. For example, in some insects, scarce nutrients induce a hormone to block tissue formation.