The regulation of Notch signaling in muscle stem cell activation and postnatal myogenesis.
ABSTRACT The Notch signaling pathway is an evolutionarily conserved pathway that is critical for tissue morphogenesis during development, but is also involved in tissue maintenance and repair in the adult. In skeletal muscle, regulation of Notch signaling is involved in somitogenesis, muscle development, and the proliferation and cell fate determination of muscle stems cells during regeneration. During each of these processes, the spatial and temporal control of Notch signaling is essential for proper tissue formation. That control is mediated by a series of regulatory proteins and protein complexes that enhance or inhibit Notch signaling by regulating protein processing, localization, activity, and stability. In this review, we focus on the regulation of Notch signaling during postnatal muscle regeneration when muscle stem cells ("satellite cells") must activate, proliferate, progress along a myogenic lineage pathway, and ultimately differentiate to form new muscle. We review the regulators of Notch signaling, such as Numb and Deltex, that have documented roles in myogenesis as well as other regulators that may play a role in modulating Notch signaling during satellite cell activation and postnatal myogenesis.
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ABSTRACT: Nandrolone, an anabolic steroid, slows denervation atrophy of rat muscle, prevents denervation-induced nuclear accumulation of intracellular domain of the Notch receptor (NICD) and elevates expression of Numb. Numb acts as an inhibitor of Notch signaling and promotes myogenic differentiation of satellite cells. Turnover of Numb is regulated by mdm2, an E3 ubiquitin ligase. With these considerations in mind, we investigated the effects of nandrolone on the expression of Numb and mdm2 proteins and determined the effect of mdm2 on nandrolone-induced alterations in Numb protein in C2C12 myoblasts. When C2C12 cells were cultured in a medium favoring differentiation [DMEM containing 2% horse serum (HS)], nandrolone upregulated Numb protein levels in a time-dependent manner and prolonged Numb protein half-life from 10h to 18h. In contrast, nandrolone reduced the expression of mdm2 protein. To determine whether the decreased mdm2 expression induced by nandrolone was responsible for the increased levels and prolonged half-life of Numb protein in this cell line, mdm2-siRNA was employed to inhibit mdm2 expression. Compared to cells transfected with scrambled siRNA (negative control), transfection with mdm2-siRNA increased basal Numb protein expression but abolished the further increase in Numb protein levels by nandrolone. In addition, transfection of mdm2-siRNA mimicked the effect of nandrolone to prolong the half-life of Numb protein. Moreover, when C2C12 cells were forced to over-express mdm2, there was a significant decline in the expression of both basal and inducible Numb protein. Our data suggest that nandrolone, by a novel mechanism for this agent in a muscle cell type, increases Numb protein levels in C2C12 myoblasts by stabilizing Numb protein against degradation, at least in part, via suppression of mdm2 expression.Journal of Andrology 06/2012; 33(6). DOI:10.2164/jandrol.112.016428 · 1.69 Impact Factor
Article: Notch signaling and cardiac repair[Show abstract] [Hide abstract]
ABSTRACT: Notch signaling is critical for proper heart development and recently has been reported to participate in adult cardiac repair. Notch resides at the cell surface as a single pass transmembrane receptor, transits through the cytoplasm following activation, and acts as a transcription factor upon entering the nucleus. This dynamic and widespread cellular distribution allows for potential interactions with many signaling and binding partners. Notch displays temporal as well as spatial versatility, acting as a strong developmental signal, controlling cell fate determination and lineage commitment, and playing a pivotal role in embryonic and adult stem cell proliferation and differentiation. This review serves as an update of recent literature addressing Notch signaling in the heart, with attention to findings from noncardiac research that provide clues for further interpretation of how the Notch pathway influences cardiac biology. Specific areas of focus include Notch signaling in adult myocardium following pathologic injury, the role of Notch in cardiac progenitor cells with respect to differentiation and cardiac repair, crosstalk between Notch and other cardiac signaling pathways, and emerging aspects of noncanonical Notch signaling in heart.Journal of Molecular and Cellular Cardiology 03/2012; 52(6):1226-32. DOI:10.1016/j.yjmcc.2012.03.007 · 5.22 Impact Factor
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ABSTRACT: Rhabdomyosarcoma (RMS) is the most common type of soft tissue sarcoma in children. Regarding histopathological criteria, RMS can be divided into 2 main subtypes: embryonal and alveolar. These subtypes differ considerably in their clinical phenotype and molecular features. Abnormal regulation or mutation of signalling pathways that regulate normal embryonic development such as Notch, Hedgehog, and Wnt is a recurrent feature in tumorigenesis. Herein, the general features of each of the three pathways, their implication in cancer and particularly in RMS are reviewed. Finally, the cross-talking among these three pathways and the possibility of better understanding of the horizontal communication among them, leading to the development of more potent therapeutic approaches, are discussed.Sarcoma 03/2012; 2012:695603. DOI:10.1155/2012/695603