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Alon Kahana, Daniel S. Kasprick, Steven Grzegorski, Tyler L. Junttila, Lindsay A. Ward, Phillip E. Kish; Myocyte Dedifferentiation Underlies Zebrafish Extraocular Muscle Regeneration: An Expanding Paradigm For Therapeutic Tissue Regeneration. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2220.
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© ARVO (1962-2015); The Authors (2016-present)
Strabismus from EOM dysfunction is a leading cause of vision loss. We discovered that adult zebrafish EOMs can regenerate following near-total myectomy, and set to determine the molecular mechanisms underlying this EOM regeneration.
We used microarray and qPCR transcriptome analysis of regenerating adult EOMs, followed by DIC microscopy, in situ hybridization and immunofluorescence to characterize gene expression during the regeneration process. Electroporation of morpholino antisense oligonucleotides enables testing the role of genes in the regeneration process.
We found that the regeneration process begins with dedifferentiation of extant myocytes, including sarcomere disassembly. Induction of twist gene expression protects the dedifferentiated progenitor cells from apoptosis, while cadherin expression pattern is consistent with collective cell migration of dedifferentiated progenitor cells. Redifferentiation proceeds via pitx3 and myod expression, and reinnervation results in fully functional regenerated EOMS, as noted by recovery of optokinetic response.
Despite the absence of pax7+ satellite cells, adult zebrafish EOM have a robust capacity to regenerate. This process is driven by dedifferentiation of extant myocytes, which display the necessary proliferative capacity. The ability of adult muscles to regenerate in zebrafish as opposed to mammals may be the result of this capacity to dedifferentiate. Identifying factors that facilitate the process may lead to development of novel therapies for human muscle injuries and degenerative conditions, particularly in strabismic conditions.
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