Xirp Proteins Mark Injured Skeletal Muscle in Zebrafish

University of Sheffield, United Kingdom
PLoS ONE (Impact Factor: 3.23). 02/2012; 7(2):e31041. DOI: 10.1371/journal.pone.0031041
Source: PubMed


Myocellular regeneration in vertebrates involves the proliferation of activated progenitor or dedifferentiated myogenic cells that have the potential to replenish lost tissue. In comparison little is known about cellular repair mechanisms within myocellular tissue in response to small injuries caused by biomechanical or cellular stress. Using a microarray analysis for genes upregulated upon myocellular injury, we identified zebrafish Xin-actin-binding repeat-containing protein1 (Xirp1) as a marker for wounded skeletal muscle cells. By combining laser-induced micro-injury with proliferation analyses, we found that Xirp1 and Xirp2a localize to nascent myofibrils within wounded skeletal muscle cells and that the repair of injuries does not involve cell proliferation or Pax7(+) cells. Through the use of Xirp1 and Xirp2a as markers, myocellular injury can now be detected, even though functional studies indicate that these proteins are not essential in this process. Previous work in chicken has implicated Xirps in cardiac looping morphogenesis. However, we found that zebrafish cardiac morphogenesis is normal in the absence of Xirp expression, and animals deficient for cardiac Xirp expression are adult viable. Although the functional involvement of Xirps in developmental and repair processes currently remains enigmatic, our findings demonstrate that skeletal muscle harbours a rapid, cell-proliferation-independent response to injury which has now become accessible to detailed molecular and cellular characterizations.

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    • "In addition to those discussed above, an increasing number of groups have utilized zebrafish to study regenerative repair after injury induced by a variety of methods in a broad array of organs, ranging from muscle repair after crush- or laser-induced injuries (Otten et al., 2012; Rodrigues et al., 2012; Seger et al., 2011) and retina regeneration after focused light injury (Ramachandran et al., 2011) to the pancreas following genetic ablation (Andersson et al., 2012; Moss et al., 2009; Pisharath et al., 2007) and scales (skin) after physical removal (de Vrieze et al., 2014). Together, these studies highlight the growing field of regenerative medicine in zebrafish, which will enable the elucidation of signals that make repair possible in those organs that typically do not regenerate in mammals, and identify novel molecules to directly enhance regenerative processes already utilized in clinical medicine today. "
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    ABSTRACT: Regenerative medicine has the promise to alleviate morbidity and mortality caused by organ dysfunction, longstanding injury and trauma. Although regenerative approaches for a few diseases have been highly successful, some organs either do not regenerate well or have no current treatment approach to harness their intrinsic regenerative potential. In this Review, we describe the modeling of human disease and tissue repair in zebrafish, through the discovery of disease-causing genes using classical forward-genetic screens and by modulating clinically relevant phenotypes through chemical genetic screening approaches. Furthermore, we present an overview of those organ systems that regenerate well in zebrafish in contrast to mammalian tissue, as well as those organs in which the regenerative potential is conserved from fish to mammals, enabling drug discovery in preclinical disease-relevant models. We provide two examples from our own work in which the clinical translation of zebrafish findings is either imminent or has already proven successful. The promising results in multiple organs suggest that further insight into regenerative mechanisms and novel clinically relevant therapeutic approaches will emerge from zebrafish research in the future.
    Full-text · Article · Jul 2014 · Disease Models and Mechanisms
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    • "We also examined the expression of xirp2a (Xin actin binding repeatcontaining protein 2 alpha), an actin-binding multi-adaptor protein found in myosepta (Otten et al., 2012). xirp2a is expressed at all sites of muscle-muscle and muscle-cartilage attachment in the head and fin, in addition to its previously characterized myoseptal expression (see Fig. 5E) (Otten et al., 2012). Interestingly, xirp2a is expressed near the sternohyoideus attachment to the lower jaw cartilage (Fig. 1M-N, arrowhead; enlarged in 1O) and at the base of the cleithrum (Fig. 1P, arrow), but is absent from the lateral regions near the palatoquadrate. "
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    ABSTRACT: Despite the importance of tendons and ligaments for transmitting movement and providing stability to the musculoskeletal system, their development is considerably less well understood than that of the tissues they serve to connect. Zebrafish have been widely used to address questions in muscle and skeletal development, yet few studies describe their tendon and ligament tissues. We have analyzed in zebrafish the expression of several genes known to be enriched in mammalian tendons and ligaments, including scleraxis (scx), collagen 1a2 (col1a2) and tenomodulin (tnmd), or in the tendon-like myosepta of the zebrafish (xirp2a). Co-expression studies with muscle and cartilage markers demonstrate the presence of scxa, col1a2 and tnmd at sites between the developing muscle and cartilage, and xirp2a at the myotendinous junctions. We determined that the zebrafish craniofacial tendon and ligament progenitors are neural crest derived, as in mammals. Cranial and fin tendon progenitors can be induced in the absence of differentiated muscle or cartilage, although neighboring muscle and cartilage are required for tendon cell maintenance and organization, respectively. By contrast, myoseptal scxa expression requires muscle for its initiation. Together, these data suggest a conserved role for muscle in tendon development. Based on the similarities in gene expression, morphology, collagen ultrastructural arrangement and developmental regulation with that of mammalian tendons, we conclude that the zebrafish tendon populations are homologous to their force-transmitting counterparts in higher vertebrates. Within this context, the zebrafish model can be used to provide new avenues for studying tendon biology in a vertebrate genetic system.
    Preview · Article · May 2014 · Development
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    • "However, evidence for rapid recovery from slight myocellular injury within the zebrafish embryo without the involvement of cell proliferation has recently been reported. These events have been associated with positivity for Xirp (Xin-actin-binding repeat-containing protein) in the damaged area [199], which represents a unique feature with respect to mammals. Interestingly, however, the Xin proteins have also been associated with muscle regeneration in mice [200]. "
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    ABSTRACT: Skeletal myogenesis has been and is currently under extensive study in both mammals and teleosts, with the latter providing a good model for skeletal myogenesis because of their flexible and conserved genome. Parallel investigations of muscle studies using both these models have strongly accelerated the advances in the field. However, when transferring the knowledge from one model to the other, it is important to take into account both their similarities and differences. The main difficulties in comparing mammals and teleosts arise from their different temporal development. Conserved aspects can be seen for muscle developmental origin and segmentation, and for the presence of multiple myogenic waves. Among the divergences, many fish have an indeterminate growth capacity throughout their entire life span, which is absent in mammals, thus implying different post-natal growth mechanisms. This review covers the current state of the art on myogenesis, with a focus on the most conserved and divergent aspects between mammals and teleosts.
    Full-text · Article · Mar 2014 · Cellular and Molecular Life Sciences CMLS
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