Adult Muscle (months)

Figure 28.3. Relative telomerase activity in whole zebrafish embryos at various developmental stages (0, 6, 24, 48, and 72 hpf), and in skeletal muscle from adult fish of various ages (5, 15, and 24 months old) (Kishi et al., 2003). Telomerase activity was examined by TRAP assay in extracted protein samples (n = 3 in each bar). Samples of B6 mouse skeletal muscle (4 weeks old) were almost undetectable levels in telomerase activity.

including zebrafish, can regenerate multiple tissues and organs, including spinal cord, retina, heart, and fins even at mature adult stages (Keating, 2004; Poss et al., 2003). We have analyzed the age-dependent alterations in the ability of zebrafish to regenerate its caudal (tail) fin. Zebrafish fins normally regenerate rapidly following amputation. Regeneration occurs within a few weeks via processes resembling amphibian limb regeneration. Following amputation, differentiated bone cells apparently dedifferentiate and enter the cell cycle, rapidly divide, and migrate from the stump to form a regenerated blastema. Formation of the blastema is followed by a period of rapid growth with continued proliferation of some blastema cells matched by withdrawal of other cells to form new bone. There was clear difference in regeneration ability of caudal fin between young fish and old fish. This ability to regenerate declines with age in zebrafish as in most other fish reported. Thus, statistical analysis of data from the 18-month and 30-month-old fish provided baseline information for age-dependent decline of wound-healing and regenerative ability.

At the molecular levels in regeneration, previous experiments with regenerating fins in zebrafish have shown that members of the Msx family of homeodomain-containing transcription factors play key roles during blastema formation and patterning. Importantly, adult zebrafish have a remarkable capacity to regenerate the heart in a process that involves up-regulation of msxB and msxC genes. In addition, the hearts of zebrafish with mutations in the Mps1 mitotic checkpoint kinase, a critical cell cycle regulator, failed to regenerate and formed scars (Poss et al., 2003; Poss et al., 2002a; Poss et al., 2002b). Preceding Msx activation (Akimenko et al., 1995), there is a marked increase in the expression of Notch1b and DeltaC, which have been shown to be up-regulated during fin and heart regeneration (Raya et al., 2003), suggesting a role for the Notch signaling pathway in the activation of g 20

the regenerative response. In this regard, Notch activation is at the base of the decisive event for proliferation and/or differentiation in a number of resident stem cells (Conboy et al., 2005; Raya et al., 2003), including those of hematopoietic, neural, gastrointestinal, and skeletal muscle lineages. Whether such stem or progenitor cells exist in zebrafish regenerative tissues and organs, whether they play a role in the regenerative response, and whether they are the origin of constitutive telomerase activity remain to be elucidated. The involvement of the Notch signaling pathway during regeneration is of biological and biomedical importance and warrants further investigation in connection with by telomerase and telomere regulation. Thus, in the next stage of regeneration studies on zebrafish aging, it will be required to investigate the molecular network in detail, taking into consideration aging stem cells. Advances in regeneration studies in zebrafish aging will undoubtedly aid in the implementation of strategies for regenerative medicine in human aging.

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