The BMP Homolog Gbb Provides a Retrograde Signal that Regulates Synaptic Growth at the Drosophila Neuromuscular Junction

McCabe, Brian D.; Marqués, Guillermo; Haghighi, A. Pejmun; Fetter, Richard D.; Crotty, M. Lisa; Haerry, Theodore E; Goodman, Corey S.; O’Connor, Michael B.

doi:10.1016/s0896-6273(03)00426-4

Cited by 368 publications

(524 citation statements)

References 85 publications

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“…Thus, manipulations that either increase (this study) or decrease (10) muscle membrane excitability do not directly affect motoneuron synaptic growth. Finally, we note that elevated presynaptic membrane excitability may potentiate the motoneuron's responsiveness to retrograde signals from the muscle, such as the growth factors essential for normal development of the synapse (49,61). Examining whether SDN enhances or suppresses bone morphogenetic protein-or Wnt-mediated signal transduction will further resolve how synaptic growth is regulated by activity in this system.…”

Section: Discussionmentioning

confidence: 95%

“…The frequency of spontaneous synaptic potentials (similar to vertebrate miniature end-plate potentials) is a widely used measure of synaptic function (11,(47)(48)(49)(50)(51) and scales with membrane excitability. Elevated spontaneous release is also characteristic of other activity mutants with reduced K ϩ currents (46).…”

Section: Sdn Expression Enhances Neuronal Excitabilitymentioning

confidence: 99%

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Dissection of synaptic excitability phenotypes by using a dominant-negative Shaker K ⁺ channel subunit

Mosca

Carrillo

White

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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During nervous system development, synapses undergo morphological change as a function of electrical activity. In Drosophila, enhanced activity results in the expansion of larval neuromuscular junctions. We have examined whether these structural changes involve the pre-or postsynaptic partner by selectively enhancing electrical excitability with a Shaker dominant-negative (SDN) potassium channel subunit. We find that the SDN enhances neurotransmitter release when expressed in motoneurons, postsynaptic potential broadening when expressed in muscles and neurons, and selectively suppresses fast-inactivating, Shaker-mediated I A currents in muscles. SDN expression also phenocopies the canonical behavioral phenotypes of the Sh mutation. At the neuromuscular junction, we find that activity-dependent changes in arbor size occur only when SDN is expressed presynaptically. This finding indicates that elevated postsynaptic membrane excitability is by itself insufficient to enhance presynaptic arbor growth. Such changes must minimally involve increased neuronal excitability.activity ͉ behavioral genetics ͉ Drosophila E lectrical activity plays a prominent role in the development and plasticity of synapses (1-3). The glutamatergic neuromuscular junction (NMJ) of Drosophila is favorable for examining synaptogenesis and the role of electrical activity in synaptic growth and refinement (4, 5). In Drosophila, activity influences synaptic connectivity (6), size (7-9), and homeostasis (10, 11). Activity may also regulate retrograde signals that influence NMJ development (12)(13)(14). However, determining the relative contributions of pre-and postsynaptic excitability to synaptic development remains a significant challenge.Addressing this problem requires molecular tools that selectively alter excitability on either side of the synapse. Early success in suppressing excitability has involved the targeted expression of modified ion channels or receptors (10,15,16). A promising approach for enhancing electrical activity involves the dominantnegative suppression of K ϩ currents involved in membrane repolarization and excitability (17, 18).The Shaker (Sh) type I A K ϩ current of Drosophila plays a key role in regulating membrane excitability of neurons and muscles (19,20) and also influences the processing of graded potentials (21). Sh mutants have well characterized hyperactive behavioral and electrophysiological phenotypes (20,(22)(23)(24), making Sh a good candidate for dominant-negative suppression. Hyperexcitable Sh mutants, when combined with other K ϩ channel mutants such as ether-a-go-go, also have enlarged larval NMJs (7-9). However, whether these structural changes arise from pre-or postsynaptic membrane hyperexcitability has remained unresolved, because the Sh mutation affects both neurons and muscle.To dissect these changes, we have developed a Sh dominantnegative (SDN) transgene as a tool for targeted enhancement of electrical excitability. SDN effectively suppresses I A, as demonstrated by voltage-clamp analysis of muscle...

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Section: Discussionmentioning

confidence: 95%

Section: Sdn Expression Enhances Neuronal Excitabilitymentioning

confidence: 99%

Dissection of synaptic excitability phenotypes by using a dominant-negative Shaker K ⁺ channel subunit

Mosca

Carrillo

White

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…Other molecules are more directly involved in synaptogenesis, synaptic growth, or maintenance. These molecules include bone morphogenetic protein (Alberle et al, 2002;Marques et al, 2002;Rawson et al, 2003;McCabe et al, 2003;Keshishian and Kim, 2004), ubiquitin (Oh et al, 1994;DiAntonio et al, 2001;Murphey and Godenschwege, 2002;DiAntonio and Hicke, 2004), cell adhesion molecules (Washbourne et al, 2004), and Wingless signaling components (Packard et al, 2003;Charron and Tessier-Lavigne, 2005).…”

Section: Introductionmentioning

confidence: 99%

The atypical cadherin flamingo regulates synaptogenesis and helps prevent axonal and synaptic degeneration in Drosophila

Bao

Berlanga

Xue

et al. 2007

Molecular and Cellular Neuroscience

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The formation of synaptic connections with target cells and maintenance of axons are highly regulated and crucial for neuronal function. The atypical cadherin and G-protein-coupled receptor Flamingo and its orthologs in amphibians and mammals have been shown to regulate cell polarity, dendritic and axonal growth, and neural tube closure. However, the role of Flamingo in synapse formation and function and in axonal health remains poorly understood. Here we show that fmi mutations cause a significant increase in the number of ectopic synapses on muscles and result in the formation of novel en passant synapses along axons, and unique presynaptic varicosities, including active zones, within axons. fmi mutations also cause defective synaptic responses in a small subset of muscles, an agedependent loss of muscle innervation and a drastic degeneration of axons in 3 rd instar larvae without an apparent loss of neurons. Neuronal expression of Flamingo rescues all of these synaptic and axonal defects and larval lethality. Based on these observations, we propose that Flamingo is required in neurons for synaptic target selection, synaptogenesis, the survival of axons and synapses, and adult viability. These findings shed new light on a possible role for Flamingo in progressive neurodegenerative diseases.

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“…At later developmental stages, multiple TGF-β superfamily ligands are expressed in whisker follicles during the period of sensory axon innervation (12)(13)(14). Retrograde TGF-β signaling has been shown to regulate neural development in Drosophila, including the growth and plasticity of the neuromuscular junction (15)(16)(17) and the specification of FMRFamide-expressing neurons (18,19). To investigate whether whisker-derived TGF-β signaling plays an essential role in orchestrating barrelette map formation in the mouse, we deleted the gene encoding Smad4, a required downstream factor for TGF-β signal transduction, specifically in sensory neurons.…”

mentioning

confidence: 99%

Proper formation of whisker barrelettes requires periphery-derived Smad4-dependent TGF-β signaling

Silva

Hasegawa

Scott

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Mammalian somatosensory topographic maps contain specialized neuronal structures that precisely recapitulate the spatial pattern of peripheral sensory organs. In the mouse, whiskers are orderly mapped onto several brainstem nuclei as a set of modular structures termed barrelettes. Using a dual-color iontophoretic labeling strategy, we found that the precise topography of barrelettes is not a result of ordered positions of sensory neurons within the ganglion. We next explored another possibility that formation of the whisker map is influenced by periphery-derived mechanisms. During the period of peripheral sensory innervation, several TGF-β ligands are exclusively expressed in whisker follicles in a dynamic spatiotemporal pattern. Disrupting TGF-β signaling, specifically in sensory neurons by conditional deletion of Smad4 at the late embryonic stage, results in the formation of abnormal barrelettes in the principalis and interpolaris brainstem nuclei and a complete absence of barrelettes in the caudalis nucleus. We further show that this phenotype is not derived from defective peripheral innervation or central axon outgrowth but is attributable to the misprojection and deficient segregation of trigeminal axonal collaterals into proper barrelettes. Furthermore, Smad4-deficient neurons develop simpler terminal arbors and form fewer synapses. Together, our findings substantiate the involvement of whisker-derived TGF-β/Smad4 signaling in the formation of the whisker somatotopic maps.O ne prominent characteristic of the rodent whisker-somatosensory system is its precisely organized topographic sensory maps (1-3). Each whisker is innervated by peripheral axons of a subset of trigeminal sensory neurons whose cell bodies reside in the trigeminal ganglia (TG) and central axons project to the brainstem (4). Sensory afferents carrying information from individual whiskers segregate and converge to form modular structures termed barrelettes, whose spatial organization exactly mirrors that of the whiskers in the periphery (5). The barrelette map in the brainstem emerges during development and serves as a template for the subsequent generation of homologous upstream structures in the thalamus and cortex, termed barreloids and barrels, respectively (5, 6). Interestingly, induction of an extra whisker by exogenous expression of Shh during early development leads to the formation of an extra barrelette with a topographic position corresponding to that of the ectopic whisker (7). Together with other studies (8-10), these data suggest that the formation of the whisker map is under the strong instructive influence of the periphery. The whisker-derived signals regulating barrelette formation remain mostly unknown, however.Previous work showed that BMP4 signaling induces differential expression of genes in trigeminal sensory neurons innervating different areas of the face along the dorsoventral axis (11,12). At later developmental stages, multiple TGF-β superfamily ligands are expressed in whisker follicles during the period of sensory...

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The BMP Homolog Gbb Provides a Retrograde Signal that Regulates Synaptic Growth at the Drosophila Neuromuscular Junction

Cited by 368 publications

References 85 publications

Dissection of synaptic excitability phenotypes by using a dominant-negative Shaker K ⁺ channel subunit

Dissection of synaptic excitability phenotypes by using a dominant-negative Shaker K ⁺ channel subunit

The atypical cadherin flamingo regulates synaptogenesis and helps prevent axonal and synaptic degeneration in Drosophila

Proper formation of whisker barrelettes requires periphery-derived Smad4-dependent TGF-β signaling

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The BMP Homolog Gbb Provides a Retrograde Signal that Regulates Synaptic Growth at the Drosophila Neuromuscular Junction

Cited by 368 publications

References 85 publications

Dissection of synaptic excitability phenotypes by using a dominant-negative Shaker K + channel subunit

Dissection of synaptic excitability phenotypes by using a dominant-negative Shaker K + channel subunit

The atypical cadherin flamingo regulates synaptogenesis and helps prevent axonal and synaptic degeneration in Drosophila

Proper formation of whisker barrelettes requires periphery-derived Smad4-dependent TGF-β signaling

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Dissection of synaptic excitability phenotypes by using a dominant-negative Shaker K ⁺ channel subunit

Dissection of synaptic excitability phenotypes by using a dominant-negative Shaker K ⁺ channel subunit