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PMID:20147321

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Citation

Müller, JS, Jepson, CD, Laval, SH, Bushby, K, Straub, V and Lochmüller, H (2010) Dok-7 promotes slow muscle integrity as well as neuromuscular junction formation in a zebrafish model of congenital myasthenic syndromes. Hum. Mol. Genet. 19:1726-40

Abstract

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.

Links

PubMed Online version:10.1093/hmg/ddq049

Keywords

Adaptor Proteins, Signal Transducing/genetics; Adaptor Proteins, Signal Transducing/metabolism; Amino Acid Sequence; Animals; Base Sequence; DNA Primers/genetics; Fluorescent Antibody Technique; Gene Components; Gene Expression Regulation/physiology; In Situ Hybridization; Molecular Sequence Data; Muscle Proteins/metabolism; Muscle, Skeletal/innervation; Muscle, Skeletal/metabolism; Myasthenic Syndromes, Congenital/physiopathology; Neuromuscular Junction/metabolism; Neuromuscular Junction/physiopathology; Receptors, Cholinergic/metabolism; Reverse Transcriptase Polymerase Chain Reaction; Sequence Alignment; Sequence Analysis, DNA; Signal Transduction/genetics; Signal Transduction/physiology; Zebrafish; Zebrafish Proteins/genetics; Zebrafish Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DANRE:F1R1E6

involved_in

GO:0007528: neuromuscular junction development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100602-6

P

Seeded From UniProt

complete

DANRE:F1R1E6

involved_in

GO:0048741: skeletal muscle fiber development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100602-6

P

Seeded From UniProt

complete

DANRE:F6P2Z4

involved_in

GO:0007528: neuromuscular junction development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100602-6

P

Seeded From UniProt

complete

DANRE:F6P2Z4

involved_in

GO:0048741: skeletal muscle fiber development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100602-6

P

Seeded From UniProt

complete


See also

References

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