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PMID:20400459

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Citation

Dowling, JJ, Low, SE, Busta, AS and Feldman, EL (2010) Zebrafish MTMR14 is required for excitation-contraction coupling, developmental motor function and the regulation of autophagy. Hum. Mol. Genet. 19:2668-81

Abstract

Myotubularins are a family of dual-specificity phosphatases that act to modify phosphoinositides and regulate membrane traffic. Mutations in several myotubularins are associated with human disease. Sequence changes in MTM1 and MTMR14 (also known as Jumpy) have been detected in patients with a severe skeletal myopathy called centronuclear myopathy. MTM1 has been characterized in vitro and in several model systems, while the function of MTMR14 and its specific role in muscle development and disease is much less well understood. We have previously reported that knockdown of zebrafish MTM1 results in significantly impaired motor function and severe histopathologic changes in skeletal muscle that are characteristic of human centronuclear myopathy. In the current study, we examine zebrafish MTMR14 using gene dosage manipulation. As with MTM1 knockdown, morpholino-mediated knockdown of MTMR14 results in morphologic abnormalities, a developmental motor phenotype characterized by diminished spontaneous contractions and abnormal escape response, and impaired excitation-contraction coupling. In contrast to MTM1 knockdown, however, muscle ultrastructure is unaffected. Double knockdown of both MTM1 and MTMR14 significantly impairs motor function and alters skeletal muscle ultrastructure. The combined effect of reducing levels of both MTMR14 and MTM1 is significantly more severe than either knockdown alone, an effect which is likely mediated, at least in part, by increased autophagy. In all, our results suggest that MTMR14 is required for motor function and, in combination with MTM1, is required for myocyte homeostasis and normal embryonic development.

Links

PubMed PMC2883342 Online version:10.1093/hmg/ddq153

Keywords

Animals; Autophagy; Disease Models, Animal; Embryo, Nonmammalian/embryology; Embryo, Nonmammalian/metabolism; Excitation Contraction Coupling; Gene Expression Regulation, Developmental; Gene Knockout Techniques; Homeostasis; Muscle, Skeletal/physiology; Muscle, Skeletal/ultrastructure; Myopathies, Structural, Congenital/metabolism; Myopathies, Structural, Congenital/pathology; Protein Tyrosine Phosphatases, Non-Receptor/genetics; Protein Tyrosine Phosphatases, Non-Receptor/metabolism; Zebrafish/embryology; Zebrafish/genetics; Zebrafish/metabolism; Zebrafish Proteins/genetics; Zebrafish Proteins/metabolism

Significance

Annotations

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

DANRE:E7F0C5

involved_in

GO:0010506: regulation of autophagy

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100325-3,ZFIN:ZDB-MRPHLNO-100613-1

P

Seeded From UniProt

complete

DANRE:E7F0C5

involved_in

GO:0050881: musculoskeletal movement

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100613-1

P

Seeded From UniProt

complete

DANRE:E7F0C5

involved_in

GO:0046716: muscle cell cellular homeostasis

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100325-3,ZFIN:ZDB-MRPHLNO-100613-1

P

Seeded From UniProt

complete

DANRE:E7F0C5

involved_in

GO:0043009: chordate embryonic development

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100325-3,ZFIN:ZDB-MRPHLNO-100613-1

P

Seeded From UniProt

complete

DANRE:F8W5H1

involved_in

GO:0010506: regulation of autophagy

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100325-3,ZFIN:ZDB-MRPHLNO-100613-1

P

Seeded From UniProt

complete

DANRE:F8W5H1

involved_in

GO:0046716: muscle cell cellular homeostasis

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100325-3,ZFIN:ZDB-MRPHLNO-100613-1

P

Seeded From UniProt

complete

DANRE:F8W5H1

involved_in

GO:0043009: chordate embryonic development

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100325-3,ZFIN:ZDB-MRPHLNO-100613-1

P

Seeded From UniProt

complete

DANRE:Q32PM3

involved_in

GO:0010506: regulation of autophagy

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100325-3,ZFIN:ZDB-MRPHLNO-100613-1

P

Seeded From UniProt

complete

DANRE:Q32PM3

involved_in

GO:0046716: muscle cell cellular homeostasis

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100325-3,ZFIN:ZDB-MRPHLNO-100613-1

P

Seeded From UniProt

complete

DANRE:Q32PM3

involved_in

GO:0043009: chordate embryonic development

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100325-3,ZFIN:ZDB-MRPHLNO-100613-1

P

Seeded From UniProt

complete


See also

References

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