Expression of mutant Ets protein at the neuromuscular synapse causes alterations in morphology and gene expression.
The localized transcription of several muscle genes at the motor endplate is controlled by the Ets transcription factor GABP. To evaluate directly its contribution to the formation of the neuromuscular junction, we generated transgenic mice expressing a general Ets dominant-negative mutant specifically in skeletal muscle. Quantitative RT-PCR analysis demonstrated that the expression of genes containing an Ets-binding site was severely affected in the mutant mice. Conversely, the expression of other synaptic genes, including MuSK and Rapsyn, was unchanged. In these animals, muscles expressing the mutant transcription factor developed normally, but examination of the post-synaptic morphology revealed marked alterations of both the primary gutters and secondary folds of the neuromuscular junction. Our results demonstrate that Ets transcription factors are crucial for the normal formation of the neuromuscular junction. They further show that Ets-independent mechanisms control the synaptic expression of a distinct set of synaptic genes.
de Kerchove D'Exaerde
Alban
A
Laboratoire de Neurobiologie Moléculaire, CNRS URA 2182 'Récepteurs et Cognition' Institut Pasteur, 25 rue du Dr Roux, 75724 Paris cedex 15, France.
Cartaud
Jean
J
Ravel-Chapuis
Aymeric
A
Seroz
Thierry
T
Pasteau
Fabien
F
Angus
Lindsay M
LM
Jasmin
Bernard J
BJ
Changeux
Jean-Pierre
JP
Schaeffer
Laurent
L
D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D007797:Laminin / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000254:growth & development / Q000502:physiology*; D009154:Mutation; D009469:Neuromuscular Junction / Q000502:physiology* / Q000648:ultrastructure; D050787:Proto-Oncogene Protein c-ets-2; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D019076:Transgenes; D049411:Utrophin
D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C107465:ERF protein, human; C494070:Ets2 protein, mouse; D007797:Laminin; D008565:Membrane Proteins; D009124:Muscle Proteins; D050787:Proto-Oncogene Protein c-ets-2; D011518:Proto-Oncogene Proteins; D011950:Receptors, Cholinergic; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C483600:Utrn protein, mouse; D049411:Utrophin; C051609:peripheral membrane protein 43K; C058783:laminin beta2; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000110:Acetylcholinesterase