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Myotonic dystrophy protein kinase maintains organization of nuclear SC‐35 domains
Author(s) -
Harmon Erin B.,
Harmon Michelle L.,
Larsen Tricia D.,
Perryman M. Benjamin
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.lb567
Subject(s) - myotonic dystrophy , myogenesis , c2c12 , biology , messenger rna , microbiology and biotechnology , gene expression , untranslated region , skeletal muscle , gene , myocyte , genetics , endocrinology
Myotonic dystrophy (DM1) is a multi‐systemic disease caused by a triplet nucleotide repeat expansion in the 3′ untranslated region of the gene coding for myotonic dystrophy protein kinase (DMPK). DMPK mRNA transcripts containing CUG expansions accumulate in the nucleus, reducing the expression of DMPK protein in affected skeletal muscle. We have found that DMPK is a nuclear envelope (NE) protein that is critical to maintain NE integrity and is required for myotube formation. Over‐expression or depletion of DMPK disrupts nuclear structure, inducing abnormal aggregation of SC‐35 nuclear domains in C2C12 mouse myoblast nuclei. Since myogenic genes localize to SC‐35 nuclear domains during myotube differentiation, changes to SC‐35 domains would be expected to affect myogenesis. SC‐35 domains are also the intranuclear location of mutant DMPK mRNA aggregation in DM1 myocytes, so we also analyzed the transport of mRNA after SC‐35 domain aggregation. We visualized mouse DMPK mRNA in C2C12 myoblasts after SC‐35 domain disruption from human DMPK over‐expression. DMPK mRNA aggregates at disrupted SC‐35 domains, similar to the aggregation in DM1. These results suggest that DMPK regulates myogenic gene expression and the stability and structural organization of the nucleus, supporting a new model for DM1 pathophysiology based on a reduction of DMPK protein expression. This work was supported by grants from NIH (EBH, MPB).