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Dok-7 promotes slow muscle integrity as well as neuromuscular junction formation in a zebrafish model of congenital myasthenic syndromes

Lookup NU author(s): Dr Juliane Mueller, Catherine Jepson, Dr Steven Laval, Emerita Professor Katherine Bushby, Professor Volker StraubORCiD, Professor Hanns Lochmuller


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The small signalling adaptor protein Dok-7 has recently been reported as an essential protein of the neuromuscular junction (NMJ). Mutations resulting in partial loss of Dok-7 activity cause a distinct limb-girdle subtype of the inherited NMJ disorder congenital myasthenic syndromes (CMSs), whereas complete loss of Dok-7 results in a lethal phenotype in both mice and humans. Here we describe the zebrafish orthologue of Dok-7 and study its in vivo function. Dok-7 deficiency leads to motility defects in zebrafish embryos and larvae. The relative importance of Dok-7 at different stages of NMJ development varies; it is crucial for the earliest step, the formation of acetylcholine receptor (AChR) clusters in the middle of the muscle fibre prior to motor neuron contact. At later stages, presence of Dok-7 is not absolutely essential, as focal and non-focal synapses do form when Dok-7 expression is downregulated. These contacts however are smaller than in the wild-type zebrafish, reminiscent of the neuromuscular endplate pathology seen in patients with DOK7 mutations. Intriguingly, we also observed changes in slow muscle fibre arrangement; previously, Dok-7 has not been linked to functions other than postsynaptic AChR clustering. Our results suggest an additional role of Dok-7 in muscle. This role seems to be independent of the muscle-specific tyrosine kinase MuSK, the known binding partner of Dok-7 at the NMJ. Our findings in the zebrafish model contribute to a better understanding of the signalling pathways at the NMJ and the pathomechanisms of DOK7 CMSs.

Publication metadata

Author(s): Müller JS, Jepson CD, Laval SH, Bushby K, Straub V, Lochmüller H

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2010

Volume: 19

Issue: 9

Pages: 1726-1740

Print publication date: 10/02/2010

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press


DOI: 10.1093/hmg/ddq049


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Funder referenceFunder name
Science City Newcastle
Association Francaise contre les Myopathies (AFM)
MRC Centre for Neuromuscular Diseases
MU2840/1-1Deutsche Forschungsgemeinschaft