Charles Géminard

Remote Control of Insulin Secretion by Fat Cells in Drosophila

Insulin-like peptides (ILPs) couple growth, metabolism, longevity, and fertility with changes in nutritional availability. In Drosophila, several ILPs called Dilps are produced by the brain insulin-producing cells (IPCs), from which they are released into the hemolymph and act systemically. We show here that in response to nutrient deprivation, brain Dilps are no longer secreted and accumulate in the IPCs. We further demonstrate that the larval fat body, a functional homolog of vertebrate liver and white fat, couples the level of circulating Dilps with dietary amino acid levels by remotely controlling Dilp release through a TOR/RAPTOR-dependent mechanism. We finally use ex vivo tissue coculture to demonstrate that a humoral signal emitted by the fat body transits through the hemolymph and activates Dilp secretion in the IPCs. Thus, the availability of nutrients is remotely sensed in fat body cells and conveyed to the brain IPCs by a humoral signal controlling ILP release.

Drosophila ALS regulates growth and metabolism through functional interaction with insulin-like peptides.

In metazoans, factors of the insulin family control growth, metabolism, longevity, and fertility in response to environmental cues. In Drosophila, a family of seven insulin-like peptides, called Dilps, activate a common insulin receptor. Some Dilp peptides carry both metabolic and growth functions, raising the possibility that various binding partners specify their functions. Here we identify dALS, the fly ortholog of the vertebrate insulin-like growth factor (IGF)-binding protein acid-labile subunit (ALS), as a Dilp partner that forms a circulating trimeric complex with one molecule of Dilp and one molecule of Imp-L2, an IgG-family molecule distantly related to mammalian IGF-binding proteins (IGFBPs). We further show that dALS antagonizes Dilp function to control animal growth as well as carbohydrate and fat metabolism. These results lead us to propose an evolutionary perspective in which ALS function appeared prior to the separation between metabolic and growth effects that are associated with vertebrate insulin and IGFs.

Control of Metabolism and Growth Through Insulin-Like Peptides in Drosophila

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.

Diversity and convergence in the mechanisms establishing L/R asymmetry in metazoa

Differentiating left and right hand sides during embryogenesis represents a major event in body patterning. Left–Right (L/R) asymmetry in bilateria is essential for handed positioning, morphogenesis and ultimately the function of organs (including the brain), with defective L/R asymmetry leading to severe pathologies in human. How and when symmetry is initially broken during embryogenesis remains debated and is a major focus in the field. Work done over the past 20 years, in both vertebrate and invertebrate models, has revealed a number of distinct pathways and mechanisms important for establishing L/R asymmetry and for spreading it to tissues and organs. In this review, we summarize our current knowledge and discuss the diversity of L/R patterning from cells to organs during evolution.

Drosophila Left/Right Asymmetry Establishment Is Controlled by the Hox Gene Abdominal-B

In Drosophila, left/right (LR) asymmetry is apparent in the directional looping of the gut and male genitalia. The dextral orientation of the organs depends on the activity of a single gene, MyosinID (myoID), whose mutation leads to a fully inverted LR axis, thus revealing the activity of a recessive sinistral pathway. Here, we present the identification of the Hox gene Abdominal-B (Abd-B) as an upstream regulator of LR determination. This role appears distinct from its function in anteroposterior patterning. We show that the Abd-Bm isoform binds to regulatory sequences of myoID and controls MyoID expression in the organ LR organizer. Abd-Bm is also required for the sinistral pathway. Thus, when Abd-B activity is missing, no symmetry breaking occurs and flies develop symmetrically. These findings identify the Hox gene Abd-B as directing the earliest events of LR asymmetry establishment in Drosophila.

The Atypical Cadherin Dachsous Controls Left-Right Asymmetry in Drosophila

Left-right (LR) asymmetry is essential for organ development and function in metazoans, but how initial LR cue is relayed to tissues still remains unclear. Here, we propose a mechanism by which the Drosophila LR determinant Myosin ID (MyoID) transfers LR information to neighboring cells through the planar cell polarity (PCP) atypical cadherin Dachsous (Ds). Molecular interaction between MyoID and Ds in a specific LR organizer controls dextral cell polarity of adjoining hindgut progenitors and is required for organ looping in adults. Loss of Ds blocks hindgut tissue polarization and looping, indicating that Ds is a crucial factor for both LR cue transmission and asymmetric morphogenesis. We further show that the Ds/Fat and Frizzled PCP pathways are required for the spreading of LR asymmetry throughout the hindgut progenitor tissue. These results identify a direct functional coupling between the LR determinant MyoID and PCP, essential for non-autonomous propagation of early LR asymmetry.

The myosin ID pathway and left–right asymmetry in Drosophila

Drosophila is a classical model to study body patterning, however left‐right (L/R) asymmetry had remained unexplored, until recently. The discovery of the conserved myosin ID gene as a major determinant of L/R asymmetry has revealed a novel L/R pathway involving the actin cytoskeleton and the adherens junction. In this process, the HOX gene Abdominal‐B plays a major role through the control of myosin ID expression and therefore symmetry breaking. In this review, we present organs and markers showing L/R asymmetry in Drosophila and discuss our current understanding of the underlying molecular genetic mechanisms. Drosophila represents a valuable model system revealing novel strategies to establish L/R asymmetry in invertebrates and providing an evolutionary perspective to the problem of laterality in bilateria. genesis 52:471–480, 2014.

Myosin1D is an evolutionarily conserved determinant of animal Left/Right asymmetry

The establishment of Left/Right (LR) asymmetry is fundamental to animal development. While the pathways governing antero-posterior and dorso-ventral patterning are well conserved among different phyla, divergent mechanisms have been implicated in the specification of LR asymmetry in vertebrates and invertebrates. A cilia-driven, directional fluid flow is important for symmetry breaking in numerous vertebrates, including zebrafish1–10. Alternatively, LR asymmetry can be established independently of motile cilia, notably through the intrinsic chirality of the acto-myosin cytoskeleton11–18. Here we show that MyosiniD (Myo1D), which has been previously identified as a key determinant of LR asymmetry in Drosophila12,13, is essential for the formation and the function of the zebrafish LR Organizer (LRO). We show that Myo1D controls the polarity of LRO cilia and interacts functionally with the Planar Cell Polarity (PCP) gene VanGogh-like2 (Vangl2)19, to promote the establishment of a functional LRO flow. Our findings identify Myo1D as the first evolutionarily conserved determinant of LR asymmetry, and show that functional interactions between Myo1D and PCP are central to the establishment of animal LR asymmetry.

Left-Right asymmetry in Drosophila: from molecular to organism chirality

SOX2 is expressed throughout the endoderm component. We investigated the involvement of SOX2 in the foregut development using a conditional Sox2-KO mouse line, where Sox2 is inactivated specifically in the endoderm by tamoxifen administration. Endoderm specific Sox2 inactivation resulted in the fusion of esophagus and trachea, bronchi branching directly from the fused duct, and shortening of esophagus. Based on the Sox2-KO embryo phenotypes, we are investigating the following points. 1) Is the loss of Sox2 expression in foregut affect the boundary between foregut and hindgut? 2) How does the loss of SOX2 cause fusion of trachea and esophagus? 3) Are the mesenchymal components involved in the Sox2-KO phenotypes? The complementary or inversely related expression patterns of transcription factors CDX2, NKX2.1, and SOX9 with SOX2 during lung and intestine development have been reported (Que et al., 2007, Gao et al., 2009, Mahony et al., 2014). In addition, the axial identity of digestive tract is considered to be regulated by Hox genes expressed in the mesenchyme at the circumference of the endodermal duct. Investigation is underway to clarify how expression of these transcription factors are affected in the Sox2-KO embryo.