Drosophila Ankyrin 2 Is Required for Synaptic Stability

Koch, Iris; Schwarz, Heinz; Beuchle, Dirk; Goellner, Bernd; Langegger, Maria; Aberle, Hermann

doi:10.1016/j.neuron.2008.03.019

Cited by 135 publications

(191 citation statements)

References 71 publications

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“…Since elaboration of the SSR requires the presence of a presynaptic nerve terminal, abnormal retraction events can be identified as Dlg-positive PSDs that are unapposed by any presynaptic markers. This assay has been used in numerous screens to identify mutations involved in synaptic maintenance, including the Dynactin protein complex (Eaton et al 2002), the microtubule-binding protein Stathmin (Graf et al 2011), the spectrin cytoskeleton (Pielage et al 2005), Ankyrin-2 and its regulator Casein kinase 2 (Koch et al 2008;Pielage et al 2008;Bulat et al 2014), the L1-type adhesion protein Neuroglian (Enneking et al 2013), and the actin-capping protein Hu-li tai shao/Adducin (Hts/Adducin) (Pielage et al 2011). Little is known about how the balance between synapse formation and elimination is regulated during development.…”

Section: Modes Of Growth Maintenance and Plasticitymentioning

confidence: 99%

Transmission, Development, and Plasticity of Synapses

Harris¹,

2015

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Chemical synapses are sites of contact and information transfer between a neuron and its partner cell. Each synapse is a specialized junction, where the presynaptic cell assembles machinery for the release of neurotransmitter, and the postsynaptic cell assembles components to receive and integrate this signal. Synapses also exhibit plasticity, during which synaptic function and/or structure are modified in response to activity. With a robust panel of genetic, imaging, and electrophysiology approaches, and strong evolutionary conservation of molecular components, Drosophila has emerged as an essential model system for investigating the mechanisms underlying synaptic assembly, function, and plasticity. We will discuss techniques for studying synapses in Drosophila, with a focus on the larval neuromuscular junction (NMJ), a well-established model glutamatergic synapse. Vesicle fusion, which underlies synaptic release of neurotransmitters, has been well characterized at this synapse. In addition, studies of synaptic assembly and organization of active zones and postsynaptic densities have revealed pathways that coordinate those events across the synaptic cleft. We will also review modes of synaptic growth and plasticity at the fly NMJ, and discuss how pre-and postsynaptic cells communicate to regulate plasticity in response to activity. KEYWORDS FlyBook; Drosophila; synapse; neurotransmitter release; synaptic plasticity; active zone; synaptic vesicle TABLE OF CONTENTS Abstract 345Introduction 345

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Section: Modes Of Growth Maintenance and Plasticitymentioning

confidence: 99%

Transmission, Development, and Plasticity of Synapses

Harris¹,

2015

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“…Indeed, as is the case in vertebrates, loss-of-function mutations of a-and b-spectrin and ankyrin2 in Drosophila are lethal early in development (Lee et al 1993;Dubreuil et al 2000;Koch et al 2008;Pielage et al 2008). Lethality in Drosophila appears to be due to a critical requirement for ab-spectrin cytoskeleton function in neurons (Mazock et al 2010).…”

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confidence: 99%

Genetic Studies of Spectrin in the Larval Fat Body ofDrosophila melanogaster: Evidence for a Novel Lipid Uptake Apparatus

et al. 2013

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Spectrin cytoskeleton defects produce a host of phenotypes affecting the plasma membrane, cell polarity, and secretory membrane traffic. However, many of the underlying molecular mechanisms remain unexplained by prevailing models. Here we used the larval fat body of Drosophila melanogaster as a genetic model system to further elucidate mechanisms of ab-spectrin function. The results provide unexpected new insights into spectrin function as well as mechanisms of dietary fat uptake and storage. We show that loss of a-or b-spectrin in the fat body eliminated a population of small cortical lipid droplets and altered plasma membrane architecture, but did not affect viability of the organism. We present a novel model in which ab-spectrin directly couples lipid uptake at the plasma membrane to lipid droplet growth in the cytoplasm. In contrast, strong overexpression of b-spectrin caused fat body atrophy and larval lethality. Overexpression of b-spectrin also perturbed transport of dietary fat from the midgut to the fat body. This hypermorphic phenotype appears to be the result of blocking secretion of the lipid carrier lipophorin from fat cells. However, this midgut phenotype was never seen with spectrin loss of function, suggesting that spectrin is not normally required for lipophorin secretion or function. The b-spectrin hypermorphic phenotype was ameliorated by co-overexpression of a-spectrin. Based on the overexpression results here, we propose that b-spectrin family members may be prone to hypermorphic effects (including effects on secretion) if their activity is not properly regulated. MEMBERS of the spectrin and ankyrin gene families are ubiquitous in animal cells and defects in these genes are responsible for a range of inherited human disorders, including spinocerebellar ataxia type 5 (SCA5) (Ikeda et al. 2006), anemia (Lux andPalek 1995), and Duchenne muscular dystrophy (Koenig et al. 1988). In most cases, the precise molecular mechanisms underlying the disease process are incompletely understood. Spectrin and ankyrin are most familiar as components of a subplasma membrane protein scaffold known as the spectrin cytoskeleton (Baines 2010). In one long-standing hypothesis the spectrin cytoskeleton is thought to capture and stabilize interacting membrane proteins as they arrive at the cell surface, creating domains of specialized composition and function (Dubreuil 2006).Recent genetic studies in a number of model systems suggest that spectrin and ankyrin have further roles in intracellular membrane traffic (Kizhatil et al. 2007(Kizhatil et al. , 2009Ayalon et al. 2008;Stabach et al. 2008;Clarkson et al. 2010;Lorenzo et al. 2010;Tjota et al. 2011).Given the conservation of spectrin and ankyrin genes between vertebrates and invertebrates, one would expect that their functions should also be conserved. Indeed, as is the case in vertebrates, loss-of-function mutations of a-and b-spectrin and ankyrin2 in Drosophila are lethal early in development (Lee et al. 1993;Dubreuil et al. 2000;Koch et al. 2008;Pielag...

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“…Ankyrins are adaptor proteins that mediate attachment of integral membrane proteins to the underlying actin cytoskeleton. Drosophila Ank2 is a neuron-specific ankyrin (Bouley et al 2000), which is required for the proper organization of Nrg and FasII at the NMJ and for synaptic maintenance and functionality (Koch et al 2008, Pielage et al 2008. Currently, it is unknown whether Nrg is the Ank2-binding partner at the NMJ, but as Nrg is the major membrane-associated ankyrin2 ligand in Drosophila neurons (Bouley et al 2000) it is an excellent candidate for interacting with Ank2 at the NMJ.…”

Section: Cam-mediated Intracellular Signaling Activation At the Nmjmentioning

confidence: 99%

“…Currently, it is unknown whether Nrg is the Ank2-binding partner at the NMJ, but as Nrg is the major membrane-associated ankyrin2 ligand in Drosophila neurons (Bouley et al 2000) it is an excellent candidate for interacting with Ank2 at the NMJ. Ank2 removal from the presynaptic cell results in disassembly of the larval NMJ due to the retraction of the microtubule-based cytoskeleton (Koch et al 2008, Pielage et al 2008. Ank2 is also associated with b-spectrin and when bspectrin is removed from the presynaptic cell, FasII and Nrg become disorganized and eventually lose their NMJ localization.…”

Section: Cam-mediated Intracellular Signaling Activation At the Nmjmentioning

confidence: 99%

“…Interestingly, the formation of the embryonic NMJ is not affected in Ank2 mutants, but as development progresses, motoneuron axons innervating posterior segments show a decreased bouton number, which manifests as posterior paralysis in the fly. Further dissection of these Ank2-mediated synaptic disintegration may prove relevant in the context of human motor neuron conditions (Koch et al 2008). …”

Section: Cam-mediated Intracellular Signaling Activation At the Nmjmentioning

confidence: 99%

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Cell Adhesion Molecules at the Drosophila Neuromuscular Junction

Carrero-Martínez

Chiba

2009

The Sticky Synapse

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PrefaceThe molecular mechanisms, which are responsible for the functional differences between the various types of neuronal synapses, have become one of the central themes of modern neurobiology. It is becoming increasingly clear that a misregulation of synaptogenesis and synaptic remodeling and dysfunctional neuronal synapses are at the heart of several human diseases, both neurological disorders and psychiatric conditions. As synapses present specialized cellular junctions between neurons and their target cells, it may not come as a surprise that neural cell adhesion molecules (CAMs) are of special importance for the genesis and the maintenance of synaptic connections. Genes encoding adhesive molecules make up a significant portion of the human genome, and neural CAMs even have been postulated to be a major factor in the evolution of the human brain. These are just some of the many reasons why we thought a book on neural CAMs and their role in establishing and maintaining neuronal synapses would be highly appropriate for summarizing our current state of knowledge. Without question, over the near future, additional adhesive proteins will join the ranks of synaptic CAMs and our knowledge, and how these molecules enable neurons and their targets to communicate effectively will grow. We hope that this book will provide a comprehensive and timely synopsis of the role of CAMs at synaptic connections and will encourage other researchers to join this exciting field of neuroscience, which has the promise not only to yield new insights into the functioning of our brain but also to shed light on some devastating human diseases. Abstract A major goal in neuroscience is the understanding of organizational principles underlying cellular communication and the ensuing molecular integrations that lead to a functional nervous system. The establishment of neuromuscular connections (junctions) is a complex process that requires enumerable cellular and molecular interactions. There are many known and well-characterized molecular events involved in every aspect of neuromuscular junction (NMJ) formation. For instance, at the presynaptic side the motoneuron must differentiate, polarize, undergo dendrogenesis and axogenesis, and extend its processes out to the muscle field. This requires axon guidance, pathfinding, and finally synaptogenesis. At the postsynaptic side, the muscle cell must differentiate and find its correct place in the embryonic body plan to receive motor axons. There are many molecules known to play essential roles during each step in these self-organizational processes. Genetic and biochemical studies have identified molecules that facilitate accurate synaptic target recognitions, as well as those responsible for pre-and postsynaptic specializations. Cell adhesion molecules (CAMs) are known to play an essential role in establishing the NMJ. In this chapter, we begin by exploring Drosophila and its NMJ as a model system for glutamatergic synapses in the mammalian central nervous system. We continue by discussing sele...

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Drosophila Ankyrin 2 Is Required for Synaptic Stability

Cited by 135 publications

References 71 publications

Transmission, Development, and Plasticity of Synapses

Transmission, Development, and Plasticity of Synapses

Genetic Studies of Spectrin in the Larval Fat Body ofDrosophila melanogaster: Evidence for a Novel Lipid Uptake Apparatus

Cell Adhesion Molecules at the Drosophila Neuromuscular Junction

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