ZFIN ID: ZDB-PUB-100223-5
Dok-7 promotes slow muscle integrity as well as neuromuscular junction formation in a zebrafish model of congenital myasthenic syndromes
Müller, J.S., Jepson, C.D., Laval, S.H., Bushby, K., Straub, V., and Lochmüller, H.
Date: 2010
Source: Human molecular genetics   19(9): 1726-1740 (Journal)
Registered Authors:
Keywords: none
MeSH Terms:
  • 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*
PubMed: 20147321 Full text @ Hum. Mol. Genet.
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.