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Clarifying the Molecular Events of Early Myofibrillogenesis in Zebrafish Open Access


Other title
muscle development
early myogenesis
Type of item
Degree grantor
University of Alberta
Author or creator
Myhre, Layne
Supervisor and department
Pilgrim, David (Biological Sciences)
Examining committee member and department
Moerman, Donald (External, UBC)
Wevrick, Rachel (Medical Genetics)
Waskiewicz, Andrew (Biological Sciences)
King-Jones, Kirst (Biological Sciences)
Department of Biological Sciences
Molecular Biology and Genetics
Date accepted
Graduation date
Doctor of Philosophy
Degree level
Sarcomeres are highly-structured protein arrays, consisting of precisely-aligned thick and thin filaments. The contractile mechanisms of sarcomeres are generally well understood, but how their patterning is initiated during early striated muscle development remains uncertain. Two of the most widely-accepted hypotheses for this process include the “molecular ruler” model, in which the massive protein titin provides a scaffold along which the myosin thick filament is assembled, and t he “pre-myofibril” model, which proposes that thick filament formation rather involves “pre-myofibril” templates, modified stress fibers consisting of non-muscle myosin (NMM) and cytoskeletal actin. These models have proven difficult to test in vivo, but zebrafish motility mutants with developmental defects in sarcomere patterning are useful for the elucidation of such mechanisms. One such mutant, steif, lacks Unc45b, a molecular chaperone that mediates the folding of thick-filament myosin during sarcomere formation. However, Unc45b may also mediate specific functions of NMMs, and unc45b mutants display myocyte detachment, indicative of dysfunctional adhesion complex formation. Given the necessity for non-muscle myosin function in the formation of adhesion complexes and pre-myofibril templates, we tested the hypothesis that the unc45b mutant phenotype is not mediated solely by interaction with muscle myosin. Our results demonstrate co-expression and co-localization of Unc45b and NMM in myogenic tissue several hours before any muscle myosin is expressed. We also noted deficiencies in the localization of adhesion complex components and NMM in unc45b mutants, that areconsistent with a NMM-mediated role for Unc45b during early myogenesis. Further, we report the analysis of the previously uncharacterized herzschlag mutant, which has similar striated muscle deficits. The herzschlag mutant produces a truncated titin protein, lacking the C-terminal rod domain that is proposed to act as a thick filament scaffold, yet muscle patterning was still initiated, with grossly normal thick and thin filament assembly. Only after embryonic muscle contraction begins is breakdown of sarcomeric myosin patterning observed, consistent with a role for titin in maintaining the contractile integrity of mature sarcomeres. These results support the pre-myofibril model, and conflict with the molecular ruler model of early sarcomere patterning, while demonstrating a novel role for Unc45b in early myogenesis.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Myhre, J.L., and D.B. Pilgrim. 2010. Cellular differentiation in primary cell cultures from single zebrafish embryos as a model for the study of myogenesis. Zebrafish. 7:255-266. Myhre, J.L., and D.B. Pilgrim. 2012. At the Start of the Sarcomere: A Previously Unrecognized Role for Myosin Chaperones and Associated Proteins during Early Myofibrillogenesis. Biochem Res Int. 2012:712315.

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