Genetic Dissection of Structural and Functional Components of Synaptic Plasticity. I. Fasciclin II Controls Synaptic Stabilization and Growth

Schuster, Christoph; Davis, Graeme W.; Fetter, Richard D.; Goodman, Corey S.

doi:10.1016/s0896-6273(00)80197-x

Cited by 489 publications

(441 citation statements)

References 37 publications

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“…3). This result is in accord with the correlation between bouton number and muscle size observed in D. melanogaster throughout larval development and reflects the fact that as muscles increase in size they require more neurotransmitter release from presynaptic motor terminals to drive their contraction (11). Nonetheless, the value of r 2 for the correlation between bouton number and muscle size for NMJ4 among the different species (Fig.…”

Section: Nmj Morphology Shows Extensive Phenotypic Variation Amongsupporting

confidence: 85%

Extensive morphological divergence and rapid evolution of the larval neuromuscular junction in Drosophila

Campbell¹,

Ganetzky

2012

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

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Although the complexity and circuitry of nervous systems undergo evolutionary change, we lack understanding of the general principles and specific mechanisms through which it occurs. The Drosophila larval neuromuscular junction (NMJ), which has been widely used for studies of synaptic development and function, is also an excellent system for studies of synaptic evolution because the genus spans >40 Myr of evolution and the same identified synapse can be examined across the entire phylogeny. We have now characterized morphology of the NMJ on muscle 4 (NMJ4) in >20 species of Drosophila. Although there is little variation within a species, NMJ morphology and complexity vary extensively between species. We find no significant correlation between NMJ phenotypes and phylogeny for the species examined, suggesting that drift alone cannot explain the phenotypic variation and that selection likely plays an important role. However, the nature of the selective pressure is still unclear because basic parameters of synaptic function remain uniform. Whatever the mechanism, NMJ morphology is evolving rapidly in comparison with other morphological features because NMJ phenotypes differ even between several sibling species pairs. The discovery of this unexpectedly extensive divergence in NMJ morphology among Drosophila species provides unique opportunities to investigate mechanisms that regulate synaptic growth; the interrelationships between synaptic morphology, neural function, and behavior; and the evolution of nervous systems and behavior in natural populations.O ver the course of evolution, the complex circuitry of nervous systems is modified both by the addition of new types of neurons and by alterations in the synaptic connectivity of preexisting neurons (1). These changes presumably provide the physical basis for acquisition of new behaviors that serve adaptive functions as new species evolve. Although the evolution of brains and behaviors is of fundamental biological importance, we lack comprehensive understanding of the general principles governing these processes or the specific mechanisms and molecules through which evolutionary changes are effected. Because synapses are the basic structural and functional units of nervous systems, one way to begin to address these problems is to investigate a defined synapse across evolutionary time, which allows us to correlate morphological variation with genetic differences.The Drosophila larval neuromuscular junction (NMJ) is a powerful system for investigating molecular mechanisms of synaptic growth and development. The muscles are large, arranged in an invariant, segmentally repeating pattern, and each muscle is innervated by the same identified motor neurons and forms NMJs with stereotypic morphology in each animal. These NMJs are large, easily accessible for microscopic and electrophysiological analyses, and their morphological features, such as the number of synaptic boutons and branch points, can be readily observed and quantified. A number of investigators have taken adva...

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Section: Nmj Morphology Shows Extensive Phenotypic Variation Amongsupporting

confidence: 85%

Extensive morphological divergence and rapid evolution of the larval neuromuscular junction in Drosophila

Campbell¹,

Ganetzky

2012

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

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“…1C). Using a different fly muscle-specific driver, Mhc-Gal4 (22), to target skd mRNA, we observed that Mhc>skd RNAi flies also displayed increased total triglycerides (Fig. 1D).…”

Section: Resultsmentioning

confidence: 98%

Heart- and muscle-derived signaling system dependent on MED13 and Wingless controls obesity in Drosophila

Lee

Bassel‐Duby

Olson

2014

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

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Obesity develops in response to an imbalance of energy homeostasis and whole-body metabolism. Muscle plays a central role in the control of energy homeostasis through consumption of energy and signaling to adipose tissue. We reported previously that MED13, a subunit of the Mediator complex, acts in the heart to control obesity in mice. To further explore the generality and mechanistic basis of this observation, we investigated the potential influence of MED13 expression in heart and muscle on the susceptibility of Drosophila to obesity. Here, we show that heart/muscle-specific knockdown of MED13 or MED12, another Mediator subunit, increases susceptibility to obesity in adult flies. To identify possible muscle-secreted obesity regulators, we performed an RNAi-based genetic screen of 150 genes that encode secreted proteins and found that Wingless inhibition also caused obesity. Consistent with these findings, muscle-specific inhibition of Armadillo, the downstream transcriptional effector of the Wingless pathway, also evoked an obese phenotype in flies. Epistasis experiments further demonstrated that Wingless functions downstream of MED13 within a muscle-regulatory pathway. Together, these findings reveal an intertissue signaling system in which Wingless acts as an effector of MED13 in heart and muscle and suggest that Wingless-mediated cross-talk between striated muscle and adipose tissue controls obesity in Drosophila. This signaling system appears to represent an ancestral mechanism for the control of systemic energy homeostasis.O besity is a systemic disorder caused by an energy imbalance in which energy input exceeds energy utilization, resulting in accumulation of excess body fat. Muscle plays a central role in systemic energy homeostasis by consuming nutrients and signaling in an endocrine manner to other tissues (1-3). Thus, there has been intense interest in identifying secreted factors from muscle that modulate the function of adipose tissue.Previously, we reported that cardiac deletion of MED13, a subunit of the Mediator complex, increases susceptibility to obesity in mice whereas cardiac overexpression of MED13 confers a lean phenotype (4), revealing an unforeseen function of the heart as a systemic regulator of energy homeostasis. The Mediator is a conserved multisubunit complex that mediates the interaction between RNA polymerase II and transcription factors and therefore governs transcription in all eukaryotes (5). MED13 and MED12 are among four subunits of the auxiliary kinase module, which confers additional regulatory functions to the Mediator complex (6). Expression profiling of yeast mutants or gene-depleted Drosophila cell lines revealed a close correlation between the gene-expression programs controlled by MED13 and MED12, suggesting their concerted actions in gene regulation (7,8).Drosophila provides a powerful model system for the genetic analysis of obesity (9-11). The processes that regulate energy homeostasis, such as energy storage and mobilization of fat in adipose tissue of the fat bo...

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“…As discussed above, synapse stability and synapse expansion during muscle growth at the NMJ are regulated by changes in FasII expression at pre-and postsynaptic membranes, and FasII expression is in part controlled by electrical activity (Schuster et al, 1996b;Ashley et al, 2005). One mechanism through which electrical activity alters FasII levels is by regulating its synaptic clustering via CaMKII-dependent phosphorylation of Dlg (Thomas et al, 1997;Koh et al, 1999).…”

Section: Ras/mapkmentioning

confidence: 99%

“…FasII has been shown to behave as a signaling molecule in early development (Garcia-Alonso et al, 1995) and to be required for memory formation in the adult (Cheng et al, 2001). In the complete absence of FasII, synapses initially form but retract early in development suggesting an essential role in NMJ maintenance (Schuster et al, 1996b). Alterations in the level of FasII during development have profound consequences for the structure and function of the synapse.…”

Section: Cell Adhesion Moleculesmentioning

confidence: 99%

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Plasticity and Second Messengers During Synapse Development

Griffith

Budnik

2006

International Review of Neurobiology

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Effective function of the locomotor system in the Drosophila larva requires a continuous adjustment of synaptic architecture and neurotransmission at the neuromuscular junction (NMJ). This feature has made the larval NMJ a favorite model to study the genetic and molecular mechanisms underlying synapse plasticity. This chapter will review experimental strategies used to study plasticity at the NMJ, the cellular parameters affected during plastic changes, and many of the known molecules involved in plastic changes. In addition, signal transduction pathways activated during plasticity will be discussed.

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Genetic Dissection of Structural and Functional Components of Synaptic Plasticity. I. Fasciclin II Controls Synaptic Stabilization and Growth

Cited by 489 publications

References 37 publications

Extensive morphological divergence and rapid evolution of the larval neuromuscular junction in Drosophila

Extensive morphological divergence and rapid evolution of the larval neuromuscular junction in Drosophila

Heart- and muscle-derived signaling system dependent on MED13 and Wingless controls obesity in Drosophila

Plasticity and Second Messengers During Synapse Development

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