Publication Date:
2012-03-20
Description:
The basic unit of skeletal muscle in all metazoans is the multinucleate myofibre, within which individual nuclei are regularly positioned. The molecular machinery responsible for myonuclear positioning is not known. Improperly positioned nuclei are a hallmark of numerous diseases of muscle, including centronuclear myopathies, but it is unclear whether correct nuclear positioning is necessary for muscle function. Here we identify the microtubule-associated protein ensconsin (Ens)/microtubule-associated protein 7 (MAP7) and kinesin heavy chain (Khc)/Kif5b as essential, evolutionarily conserved regulators of myonuclear positioning in Drosophila and cultured mammalian myotubes. We find that these proteins interact physically and that expression of the Kif5b motor domain fused to the MAP7 microtubule-binding domain rescues nuclear positioning defects in MAP7-depleted cells. This suggests that MAP7 links Kif5b to the microtubule cytoskeleton to promote nuclear positioning. Finally, we show that myonuclear positioning is physiologically important. Drosophila ens mutant larvae have decreased locomotion and incorrect myonuclear positioning, and these phenotypes are rescued by muscle-specific expression of Ens. We conclude that improper nuclear positioning contributes to muscle dysfunction in a cell-autonomous fashion.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321085/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321085/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Metzger, Thomas -- Gache, Vincent -- Xu, Mu -- Cadot, Bruno -- Folker, Eric S -- Richardson, Brian E -- Gomes, Edgar R -- Baylies, Mary K -- GM056989/GM/NIGMS NIH HHS/ -- GM0781318/GM/NIGMS NIH HHS/ -- R01 GM056989/GM/NIGMS NIH HHS/ -- R01 GM056989-09/GM/NIGMS NIH HHS/ -- R01 GM078318/GM/NIGMS NIH HHS/ -- R01 GM078318-04/GM/NIGMS NIH HHS/ -- T32 BM008539/BM/FDA HHS/ -- England -- Nature. 2012 Mar 18;484(7392):120-4. doi: 10.1038/nature10914.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Program in Developmental Biology, Sloan-Kettering Institute, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22425998" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Cell Compartmentation/genetics
;
Cell Line
;
Cell Nucleus/*metabolism
;
Cell Polarity/genetics
;
Cells, Cultured
;
Drosophila melanogaster/cytology/genetics/growth & development
;
Kinesin/chemistry/deficiency/genetics/*metabolism
;
Larva/cytology/genetics/metabolism
;
Locomotion/genetics/physiology
;
Mice
;
Microtubule-Associated Proteins/chemistry/genetics/*metabolism
;
Microtubules/metabolism
;
Muscle Fibers, Skeletal/cytology/metabolism
;
Muscle, Skeletal/*cytology/*physiology
;
Organ Specificity
;
Phenotype
;
Protein Binding
;
Protein Structure, Tertiary
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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