Abstract
We are interested in how the genetic basis of muscle precursor cells determines the outcome of the muscle cell fate, and thus leading to disruption in muscle formation and maintenance. We utilized the zebrafish carrying mutations in both Axin1 and Apc1, resulting in overactivation of the Wnt/beta-catenin signaling pathway. We
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discovered that loss of function of these two genes results in aberrant muscle fiber formation in zebrafish embryos, differentially affecting fast and slow muscle fibers. The aberrant fast muscle development in gain-of-Wnt/beta-catenin-function derives from hyperproliferating pre-myogenic progenitors. Chemical intervention that attenuates hyperproliferation rescues fast muscle fibers to normality. Epistatic analyses show that normal fast muscle myofibrillogenesis requires (a) restriction of Wnt/beta-catenin signaling and the corresponding upregulation of Myostatin; (b) Myostatin functions in the same process in a negative-feedback loop to repress the Wnt/beta-catenin pathway. The downstream target of Wnt/beta-catenin in this process is p21CIP/WAF, which is known to be downstream of Myostatin. Next, we investigated the role of Asb11, a positive regulator of Notch signaling pathway, in embryonic and adult muscle development. Our group has previously reported the role of Asb11 in maintenance of the neural progenitor compartment. We showed that an intact Asb11 protein Is required for proper myogenesis to proceed. In adult muscles, Asb11 co-localized with a subpopulation of Pax7 cells, a marker for muscle progenitor and stem cells. Long-term BrdU retaining cells, which are slow cycling, co-localizes with Asb11 cells, suggesting a stem cell-like role of Asb11 in adult myogenesis. Furthermore, we observed a less efficient regeneration in Asb11 adult zebrafish mutants. These mutants lack a Cullin box domain which we reported to be functionally important in vivo for Notch signalling activation and cell fate specification. Finally, we described a role of Asb11 in myogenic differentiation, both in vitro and in vivo. We provide evidence that d-Asb11/h-ASB9 expression delays expression of muscle creatine kinase (CKM) during myogenic differentiation in a seemingly Notch-independent fashion. Thus, these results support the notion that the signaling mechanisms involved in the regulation of muscle compartment size can apparently involve Notch-dependent and independent pathways.
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