Jean-Baptiste Coutelis

Coupling of Apoptosis and L/R Patterning Controls Stepwise Organ Looping

Handed asymmetry in organ shape and positioning is a common feature among bilateria, yet little is known about the morphogenetic mechanisms underlying left-right (LR) organogenesis. We utilize the directional 360° clockwise rotation of genitalia in Drosophila to study LR-dependent organ looping. Using time-lapse imaging, we show that rotation of genitalia by 360° results from an additive process involving two ring-shaped domains, each undergoing 180° rotation. Our results show that the direction of rotation for each ring is autonomous and strictly depends on the LR determinant myosin ID (MyoID). Specific inactivation of MyoID in one domain causes rings to rotate in opposite directions and thereby cancels out the overall movement. We further reveal a specific pattern of apoptosis at the ring boundaries and show that local cell death is required for the movement of each domain, acting as a brake-releaser. These data indicate that organ looping can proceed through an incremental mechanism coupling LR determination and apoptosis. Furthermore, they suggest a model for the stepwise evolution of genitalia posture in Diptera, through the emergence and duplication of a 180° LR module.

Left-right asymmetry in Drosophila.

Seminal studies of left-right (L/R) patterning in vertebrate models have led to the discovery of roles for the nodal pathway, ion flows and cilia in this process. Although the molecular mechanisms underlying L/R asymmetries seen in protostomes are less well understood, recent work using Drosophila melanogaster as a novel genetic model system to study this process has identified a number of mutations affecting directional organ looping. The genetic analysis of this, the most evolutionary conserved feature of L/R patterning, revealed the existence of a L/R pathway that involves the actin cytoskeleton and an associated type I myosin. In this review, we describe this work in the context of Drosophila development, and discuss the implications of these results for our understanding of L/R patterning in general.

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.