Mutations in the Caenorhabditis elegans dystrophin-like gene dys-1 lead to hyperactivity and suggest a link with cholinergic transmission

Abstract

Mutations in the human dystrophin gene cause Duchenne muscular dystrophy, a common neuromuscular disease leading to a progressive necrosis of muscle cells. The etiology of this necrosis has not been clearly established, and the cellular function of the dystrophin protein is still unknown. We report here the identification of a dystrophin-like gene (named dys-1) in the nematode Caenorhabditis elegans. Loss-of-function mutations of the dys-1 gene make animals hyperactive and slightly hypercontracted. Surprisingly, the dys-1 mutants have apparently normal muscle cells. Based on reporter gene analysis and heterologous promoter expression, the site of action of the dys-1 gene seems to be in muscles. A chimeric transgene in which the C-terminal end of the protein has been replaced by the human dystrophin sequence is able to partly suppress the phenotype of the dys-1 mutants, showing that both proteins share some functional similarity. Finally, the dys-1 mutants are hypersensitive to acetylcholine and to the acetylcholinesterase inhibitor aldicarb, suggesting that dys-1 mutations affect cholinergic transmission. This study provides the first functional link between the dystrophin family of proteins and cholinergic transmission.

DYC-1, a Protein Functionally Linked to Dystrophin inCaenorhabditis elegansIs Associated with the Dense Body, Where It Interacts with the Muscle LIM Domain Protein ZYX-1

“…dys-1 mutants develop a peculiar phenotype consisting of hyperactivity, exaggerated head bending and a tendency to hypercontract (Bessou et al, 1998). These mutants undergo only slight muscle degeneration (Bessou et al, 1998;Grisoni et al, 2003).…”

“…These mutants undergo only slight muscle degeneration (Bessou et al, 1998;Grisoni et al, 2003). However, in a sensitized hlh-1(cc561) background, which is a mild mutation of the C. elegans homologue of the myogenic factor MyoD, dys-1 mutations lead to an extensive time-dependent muscle degeneration (Gieseler et al, 2000).…”

Duchenne Muscular Dystrophy: Stalled at the junction?

“…2 To our surprise, null mutations of the so-called dys-1 gene left the C. elegans muscles almost unaffected, but resulted in hyperactivity and a tendency to hypercontract. Moreover, the dys-1 mutants were hypersensitive to Ach and to the drug aldicarb, which is used in C. elegans as an indirect measurement of cholinergic activity.…”

“…The most straightforward interpretation of this phenotype was -and remainsthat the absence of dystrophin upregulates cholinergic transmission in C. elegans. 2 It was later shown that acetylcholinesterase (AchE) activity was slightly reduced in dys-1 mutants. 3 However, since dys-1 and AchE mutants have different phenotypes in C. elegans, it was clear that additional directions had to be explored to explain the dys-1 phenotype.…”

Poriferan survivin exhibits a conserved regulatory role in the interconnected pathways of cell cycle and apoptosis

“…2 In addition, loss-of-function mutations of the C. elegans dystrophin-1 gene confirmed the role of human dystrophin in the manifestation of the neuromuscular disease of Duchenne. 3 During the last years a novel invertebrate model system has emerged: sponges (phylum Porifera), which are among the earliest-branching nonbilaterian animals. 4 Recent biomarker analyses date the occurrence of probable stem-group poriferans back before the end of the Marinoan glaciation (B635 Myr ago) 5 and molecular clock analyses estimated that the main poriferan lineages diverged in the Cryogenian/ Ediacaran, 6 well before the rapid appearance of major metazoan groups (Cambrian Explosion).…”