We report the identification of bang senseless (bss), a Drosophila melanogaster mutant exhibiting seizure-like behaviors, as an allele of the paralytic (para) voltage-gated Na 1 (Na V ) channel gene. Mutants are more prone to seizure episodes than normal flies because of a lowered seizure threshold. The bss phenotypes are due to a missense mutation in a segment previously implicated in inactivation, termed the ''paddle motif'' of the Na V fourth homology domain. Heterologous expression of cDNAs containing the bss 1 lesion, followed by electrophysiology, shows that mutant channels display altered voltage dependence of inactivation compared to wild type. The phenotypes of bss are the most severe of the bang-sensitive mutants in Drosophila and can be ameliorated, but not suppressed, by treatment with anti-epileptic drugs. As such, bss-associated seizures resemble those of pharmacologically resistant epilepsies caused by mutation of the human Na V SCN1A, such as severe myoclonic epilepsy in infants or intractable childhood epilepsy with generalized tonic-clonic seizures.

Despite the frequency of seizure disorders in the human population, the genetic and physiological basis for these defects has been difficult to resolve. Although many genetic contributions to seizure susceptibility have been identified, these involve disparate biological processes, many of which are not neural specific. The large number and heterogeneous nature of the genes involved makes it difficult to understand the complex factors underlying the etiology of seizure disorders. Examining the effect known genetic mutations have on seizure susceptibility is one approach that may prove fruitful. This approach may be helpful in both understanding how different physiological processes affect seizure susceptibility and identifying novel therapeutic treatments. We review here factors contributing to seizure susceptibility in Drosophila, a genetically tractable system that provides a model for human seizure disorders. Seizure-like neuronal activities and behaviors in the fruit fly are described, as well as a set of mutations that exhibit features resembling some human epilepsies and render the fly sensitive to seizures. Especially interesting are descriptions of a novel class of mutations that are second-site mutations that act as seizure suppressors. These mutations revert epilepsy phenotypes back to the wild-type range of seizure susceptibility. The genes responsible for seizure suppression are cloned with the goal of identifying targets for lead compounds that may be developed into new antiepileptic drugs.

Axon guidance is regulated by intrinsic factors and extrinsic cues provided by other neurons, glia and target muscles. Dawdle (Daw), a divergent TGF-␤ superfamily ligand expressed in glia and mesoderm, is required for embryonic motoneuron pathfinding in Drosophila. In daw mutants, ISNb and SNa axons fail to extend completely and are unable to innervate their targets. We find that Daw initiates an activin signaling pathway via the receptors Punt and Baboon (Babo) and the signal-transducer Smad2. Furthermore, mutations in these signaling components display similar axon guidance defects. Cell-autonomous disruption of receptor signaling suggests that Babo is required in motoneurons rather than in muscles or glia. Ectopic ligand expression can rescue the daw phenotype, but has no deleterious effects. Our results indicate that Daw functions in a permissive manner to modulate or enable the growth cone response to other restricted guidance cues, and support a novel role for activin signaling in axon guidance.

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Activins are members of the TGF-ss superfamily of secreted growth factors that control a diverse array of processes in vertebrates including endocrine function, cell proliferation, differentiation, immune response and wound repair. In Drosophila, the Activin ligand Dawdle (Daw) has been shown to regulate several aspects of neuronal development such as embryonic axonal pathfinding, neuroblast proliferation in the larval brain and growth cone motility in the visual system. Here we identify a novel role for Activin signaling in regulating synaptic growth at the larval neuromuscular junction (NMJ). Mutants for Daw, the Activin type I receptor Baboon (Babo), and the signal transducer dSmad2, display reduced NMJ size suggesting that Daw utilizes a canonical Activin signal-transduction pathway in this context. Additionally, loss of Daw/Babo activity affects microtubule stability, axonal transport and distribution of Futsch, the Drosophila microtubule associated protein 1B (MAP1B) homolog. We find that Babo signaling is required postsynaptically in the muscle, in contrast to the well-characterized retrograde BMP/Gbb signal that is required for synaptic growth and function in presynaptic cells. Finally, we show that the Daw/Babo pathway acts upstream of gbb, and is involved in maintenance of muscle gbb expression, suggesting that Activins regulate NMJ growth by modulating BMP activity through transcriptional regulation of ligand expression.