The zebrafish <i>ennui</i> behavioral mutation disrupts acetylcholine receptor localization and motor axon stability

Saint-Amant, Louis; Sprague, Shawn M.; Hirata, Hiromi; Li, Qin; Cui, Wilson W.; Zhou, Weibin; Poudou, Olivier; Hume, Richard I.; Kuwada, John Y.

doi:10.1002/dneu.20569

Cited by 21 publications

(23 citation statements)

References 68 publications

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“…In zebrafish, the first recognizable muscle dependent motor function, detected between 17 and 26 hpf, is spontaneous embryo coiling [21]. On average, control injected embryos had 10.2 (+/−0.4) spontaneous muscle contractions per 15 second period (Supplemental Video 1).…”

Section: Resultsmentioning

confidence: 99%

Loss of Myotubularin Function Results in T-Tubule Disorganization in Zebrafish and Human Myotubular Myopathy

et al. 2009

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Myotubularin is a lipid phosphatase implicated in endosomal trafficking in vitro, but with an unknown function in vivo. Mutations in myotubularin cause myotubular myopathy, a devastating congenital myopathy with unclear pathogenesis and no current therapies. Myotubular myopathy was the first described of a growing list of conditions caused by mutations in proteins implicated in membrane trafficking. To advance the understanding of myotubularin function and disease pathogenesis, we have created a zebrafish model of myotubular myopathy using morpholino antisense technology. Zebrafish with reduced levels of myotubularin have significantly impaired motor function and obvious histopathologic changes in their muscle. These changes include abnormally shaped and positioned nuclei and myofiber hypotrophy. These findings are consistent with those observed in the human disease. We demonstrate for the first time that myotubularin functions to regulate PI3P levels in a vertebrate in vivo, and that homologous myotubularin-related proteins can functionally compensate for the loss of myotubularin. Finally, we identify abnormalities in the tubulo-reticular network in muscle from myotubularin zebrafish morphants and correlate these changes with abnormalities in T-tubule organization in biopsies from patients with myotubular myopathy. In all, we have generated a new model of myotubular myopathy and employed this model to uncover a novel function for myotubularin and a new pathomechanism for the human disease that may explain the weakness associated with the condition (defective excitation–contraction coupling). In addition, our findings of tubuloreticular abnormalities and defective excitation-contraction coupling mechanistically link myotubular myopathy with several other inherited muscle diseases, most notably those due to ryanodine receptor mutations. Based on our findings, we speculate that congenital myopathies, usually considered entities with similar clinical features but very disparate pathomechanisms, may at their root be disorders of calcium homeostasis.

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Section: Resultsmentioning

confidence: 99%

Loss of Myotubularin Function Results in T-Tubule Disorganization in Zebrafish and Human Myotubular Myopathy

et al. 2009

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“…Other behavioral mutants exhibiting decreased synaptic transmission and clustering of nAChRs at the NMJ have also been identified including nicotinic receptor ( nic ) and sofa potato ( sop ) which harbor mutations in the nAChR α and δ subunit genes, respectively. By contrast, mutants unp and twitch-once ( two ) have mutations in the genes encoding MuSK and the AChR clustering factor rapsyn, respectively (Westerfield et al, 1990; Sepich et al, 1998; Ono et al, 2001, 2002, 2004; Saint-Amant et al, 2008). Curiously, another mutant in the ‘twitch-once’ class of motility mutants (Granato et al, 1996), shocked ( sho ), was recently shown to result from mutations in slc6a9 encoding GlyT1 (Table 2; Cui et al, 2005; Mongeon et al, 2008).…”

Section: Forward Genetics To Identify Zebrafish Mutants Showing Motilmentioning

confidence: 99%

Defective glycinergic synaptic transmission in zebrafish motility mutants

Hirata

Carta²,

Yamanaka

et al. 2010

Front. Mol. Neurosci.

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Glycine is a major inhibitory neurotransmitter in the spinal cord and brainstem. Recently, in vivo analysis of glycinergic synaptic transmission has been pursued in zebrafish using molecular genetics. An ENU mutagenesis screen identified two behavioral mutants that are defective in glycinergic synaptic transmission. Zebrafish bandoneon (beo) mutants have a defect in glrbb, one of the duplicated glycine receptor (GlyR) β subunit genes. These mutants exhibit a loss of glycinergic synaptic transmission due to a lack of synaptic aggregation of GlyRs. Due to the consequent loss of reciprocal inhibition of motor circuits between the two sides of the spinal cord, motor neurons activate simultaneously on both sides resulting in bilateral contraction of axial muscles of beo mutants, eliciting the so-called ‘accordion’ phenotype. Similar defects in GlyR subunit genes have been observed in several mammals and are the basis for human hyperekplexia/startle disease. By contrast, zebrafish shocked (sho) mutants have a defect in slc6a9, encoding GlyT1, a glycine transporter that is expressed by astroglial cells surrounding the glycinergic synapse in the hindbrain and spinal cord. GlyT1 mediates rapid uptake of glycine from the synaptic cleft, terminating synaptic transmission. In zebrafish sho mutants, there appears to be elevated extracellular glycine resulting in persistent inhibition of postsynaptic neurons and subsequent reduced motility, causing the ‘twitch-once’ phenotype. We review current knowledge regarding zebrafish ‘accordion’ and ‘twitch-once’ mutants, including beo and sho, and report the identification of a new α2 subunit that revises the phylogeny of zebrafish GlyRs.

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“…In rapsyn mutants, the postsynaptic AChR clusters are diffusely distributed and the mutant embryos are less active [46,64,68]. Similarly, zebrafish ennui mutants show reduced AChR aggregation at the NMJ and slow swimming in escape response, but the responsible gene for this mutation has not yet been determined [69]. In zebrafish, there are at least two functionally distinct splicing variants of MuSK [70].…”

Section: Zebrafish Motility Mutants Caused By Muscle or Neuromuscularmentioning

confidence: 99%

Zebrafish muscular disease models towards drug discovery

Hirata

2009

Expert Opinion on Drug Discovery

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During embryogenesis, zebrafish start to coil their body by contracting trunk muscles 17 h postfertilization, indicating that a motor circuit and skeletal muscle are functionally developed at early stages. Mutagenesis screens in zebrafish have identified many motility mutants that display morphological or functional defects in the CNS, clustering defects of acetylcholine receptors at the neuromuscular junctions or pathological defects of muscles. Most of the muscular mutants are useful as animal models of human muscle disease such as muscle dystrophy. As zebrafish live in water, pharmacological drugs are easily assayable during development, and thus zebrafish may be used to determine novel drugs that mitigate muscle disease.

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The zebrafish ennui behavioral mutation disrupts acetylcholine receptor localization and motor axon stability

Cited by 21 publications

References 68 publications

Loss of Myotubularin Function Results in T-Tubule Disorganization in Zebrafish and Human Myotubular Myopathy

Loss of Myotubularin Function Results in T-Tubule Disorganization in Zebrafish and Human Myotubular Myopathy

Defective glycinergic synaptic transmission in zebrafish motility mutants

Zebrafish muscular disease models towards drug discovery

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