title: Depletion of zebrafish Tcap leads to muscular dystrophy via disrupting sarcomere-membrane interaction, not sarcomere assembly.
abstract: Tcap/telethonin encodes a Z-disc protein that plays important roles in sarcomere assembly, sarcomere-membrane interaction and stretch sensing. It remains unclear why mutations in Tcap lead to limb-girdle muscular dystrophy 2G (LGMD2G) in human patients. Here, we cloned tcap in zebrafish and conducted genetic studies. We show that tcap is functionally conserved, as the Tcap protein appears in the sarcomeric Z-disc and reduction of Tcap resulted in muscular dystrophy-like phenotypes including deformed muscle structure and impaired swimming ability. However, the observations that Tcap integrates into the sarcomere at a stage after the Z-disc becomes periodic, and that the sarcomere remains intact in tcap morphants, suggest that defective sarcomere assembly does not contribute to this particular type of muscular dystrophy. Instead, a defective interaction between the sarcomere and plasma membrane was detected, which was further underscored by the disrupted development of the T-tubule system. Pertinent to a potential function in stretch sensor signaling, zebrafish tcap exhibits a variable expression pattern during somitogenesis. The variable expression is inducible by stretch force, and the expression level of Tcap is negatively regulated by integrin-link kinase (ILK), a protein kinase that is involved in stretch sensing signaling. Together, our genetic studies of tcap in zebrafish suggested that pathogenesis in LGMD2G is due to a disruption of sarcomere-T-tubular interaction, but not of sarcomere assembly per se. In addition, our data prompted a novel hypothesis that predicts that the transcription level of Tcap can be regulated by the stretch force to ensure proper sarcomere-membrane interaction in striated muscles.
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Ruilin
authors.initials: R
authors.lastname: Zhang
authors.forename: Jingchun
authors.initials: J
authors.lastname: Yang
authors.forename: Jin
authors.initials: J
authors.lastname: Zhu
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Xu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D064211:Connectin; D004625:Embryo, Nonmammalian / Q000196:embryology / Q000378:metabolism / Q000648:ultrastructure; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D046529:Microscopy, Electron, Transmission; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000378:metabolism; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010802:Phylogeny; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012518:Sarcomeres / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013550:Swimming; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000502:physiology; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D064211:Connectin; D009124:Muscle Proteins; C577292:TCAP protein, human; C547096:Tcap protein, zebrafish; D029961:Zebrafish Proteins; D049452:Green Fluorescent Proteins
references.citation: Hum Mol Genet. 2003 Oct 15;12 Spec No 2:R265-70
references.pmid: 14504264
references.citation: Hum Mutat. 2006 May;27(5):453-9
references.pmid: 16575835
references.citation: J Muscle Res Cell Motil. 2001;22(3):259-64
references.pmid: 11763198
references.citation: Neuromuscul Disord. 2008 Dec;18(12):929-33
references.pmid: 18948002
references.citation: J Biol Chem. 2002 Apr 19;277(16):13998-4004
references.pmid: 11842093
references.citation: Nature. 1998 Oct 29;395(6705):863-9
references.pmid: 9804419
references.citation: Curr Opin Genet Dev. 2003 Jun;13(3):231-8
references.pmid: 12787784
references.citation: Nature. 2006 Jan 12;439(7073):229-33
references.pmid: 16407954
references.citation: Circ Res. 2004 Feb 20;94(3):296-305
references.pmid: 14976140
references.citation: Development. 2005 Jul;132(13):2955-67
references.pmid: 15930106
references.citation: Genes Dev. 2006 Sep 1;20(17):2361-72
references.pmid: 16921028
references.citation: Proc Natl Acad Sci U S A. 2007 Apr 24;104(17):7092-7
references.pmid: 17438294
references.citation: Cell. 2002 Dec 27;111(7):943-55
references.pmid: 12507422
references.citation: J Biol Chem. 2003 Dec 12;278(50):50466-73
references.pmid: 14506282
references.citation: Science. 2002 Aug 16;297(5584):1193-6
references.pmid: 12183633
references.citation: J Mol Biol. 2004 May 28;339(2):313-25
references.pmid: 15136035
references.citation: Biochim Biophys Acta. 2007 Feb;1772(2):205-15
references.pmid: 16934958
references.citation: Am J Physiol Heart Circ Physiol. 2007 Dec;293(6):H3396-403
references.pmid: 17921333
references.citation: Cell. 1988 Apr 22;53(2):219-28
references.pmid: 3282674
references.citation: Cell Motil Cytoskeleton. 2005 May;61(1):34-48
references.pmid: 15810059
references.citation: Curr Opin Neurol. 2008 Oct;21(5):576-84
references.pmid: 18769252
references.citation: Hum Mol Genet. 2005 Jul 1;14(13):1727-43
references.pmid: 15888488
references.citation: FEBS Lett. 1997 Sep 29;415(2):163-8
references.pmid: 9350988
references.citation: FEBS Lett. 1998 May 22;428(1-2):111-4
references.pmid: 9645487
references.citation: J Mol Biol. 2001 Nov 2;313(4):775-84
references.pmid: 11697903
references.citation: J Biol Chem. 2001 Jun 15;276(24):21425-33
references.pmid: 11259414
references.citation: Nature. 1990 May 24;345(6273):315-9
references.pmid: 2188135
references.citation: Dev Dyn. 2009 Jun;238(6):1564-73
references.pmid: 19322764
references.citation: Development. 2003 Dec;130(23):5851-60
references.pmid: 14573513
references.citation: Circ Res. 2007 Feb 2;100(2):238-45
references.pmid: 17170364
references.citation: J Mol Med (Berl). 2003 Dec;81(12):750-6
references.pmid: 14551702
references.citation: Dev Dyn. 2006 Aug;235(8):2018-29
references.pmid: 16779859
references.citation: Circ Res. 2008 Apr 11;102(7):831-9
references.pmid: 18292601
references.citation: PLoS Genet. 2009 Feb;5(2):e1000372
references.pmid: 19197364
references.citation: J Cell Physiol. 2002 Oct;193(1):120-31
references.pmid: 12209887
references.citation: Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3710-4
references.pmid: 8475120
references.citation: Nat Genet. 2000 Feb;24(2):163-6
references.pmid: 10655062
references.citation: Nat Genet. 2000 Oct;26(2):216-20
references.pmid: 11017081
references.citation: Dev Biol. 2008 Jun 1;318(1):92-101
references.pmid: 18436206
references.citation: J Biol Chem. 2003 Feb 21;278(8):6059-65
references.pmid: 12464612
references.citation: Med Hypotheses. 2007;69(2):310-21
references.pmid: 17376604
references.citation: Circ Res. 2004 Nov 26;95(11):1091-9
references.pmid: 15514163
references.citation: Genes Dev. 2001 Nov 15;15(22):2967-79
references.pmid: 11711432
references.citation: J Mol Med (Berl). 2006 Jun;84(6):446-68
references.pmid: 16416311
references.citation: IUBMB Life. 2001 May;51(5):275-82
references.pmid: 11699871
references.citation: Nat Rev Mol Cell Biol. 2006 Oct;7(10):762-73
references.pmid: 16971897
references.citation: Science. 1989 Jun 30;244(4912):1578-80
references.pmid: 2662404
references.citation: Dev Biol. 1997 Dec 15;192(2):289-99
references.pmid: 9441668
references.citation: Biochem Biophys Res Commun. 1999 Apr 21;257(3):699-703
references.pmid: 10208846
references.citation: Neuromuscul Disord. 1997 May;7(3):191-7
references.pmid: 9185184