Abstract
Dlk1, a member of the Epidermal Growth Factor family, is expressed in multiple tissues during development, and has been detected in carcinomas and neuroendocrine tumors. Dlk1 is paternally expressed and belongs to a group of imprinted genes associated with rhabdomyosarcomas but not with other primitive childhood tumors to date. Here, we investigate the possible roles of Dlk1 in skeletal muscle tumor formation. We analyzed tumors of different mesenchymal origin for expression of Dlk1 and various myogenic markers and found that Dlk1 was present consistently in myogenic tumors. The coincident observation of Dlk1 with a highly proliferative state in myogenic tumors led us to subsequently investigate the involvement of Dlk1 in the control of the adult myogenic programme. We performed an injury study in Dlk1 transgenic mice, ectopically expressing ovine Dlk1 (membrane bound C2 variant) under control of the myosin light chain promotor, and detected an early, enhanced formation of myotubes in Dlk1 transgenic mice. We then stably transfected the mouse myoblast cell line, C2C12, with full-length Dlk1 (soluble A variant) and detected an inhibition of myotube formation, which could be reversed by adding Dlk1 antibody to the culture supernatant. These results suggest that Dlk1 is involved in controlling the myogenic programme and that the various splice forms may exert different effects. Interestingly, both in the Dlk1 transgenic mice and the DLK1-C2C12 cells, we detected reduced myostatin expression, suggesting that the effect of Dlk1 on the myogenic programme might involve the myostatin signaling pathway. In support of a relationship between Dlk1 and myostatin we detected reciprocal expression of these two transcripts during different cell cycle stages of human myoblasts. Together our results suggest that Dlk1 is a candidate marker for skeletal muscle tumors and might be involved directly in skeletal muscle tumor formation through a modulatory effect on the myogenic programme.
Highlights
Delta-Like 1 Homolog (Dlk1) is a member of the Epidermal Growth Factor family [1]
Full-length isoform A and variant B both contain a protease-recognition site and can produce a soluble form of the protein whereas C, C2, D, and D2 all remain membrane-bound [1,5]. It belongs to a group of imprinted genes, which have been associated recently with rhabdomyosarcomas but not other primitive childhood tumors [6], Dlk1 might be involved in skeletal muscle tumour formation
By showing that Dlk1 protein is present in post-natal skeletal muscle of only callipyge animals, and by producing transgenic mice that recapitulate the CLPG phenotype by ectopically expressing the ovine C2 membrane-bound isoform of Dlk1, we have shown that Dlk1 is responsible, at least in part, for the manifestation of the CLPG phenotype [8]
Summary
Dlk is a member of the Epidermal Growth Factor family [1]. It is expressed widely during development, but is detectable in only a few mature tissues including pituitary growth hormone cells, pancreatic beta cells and adrenal cortical cells [2]. Full-length isoform A and variant B both contain a protease-recognition site and can produce a soluble form of the protein whereas C, C2, D, and D2 all remain membrane-bound [1,5] It belongs to a group of imprinted genes, which have been associated recently with rhabdomyosarcomas but not other primitive childhood tumors [6], Dlk might be involved in skeletal muscle tumour formation. We demonstrated that Dlk is expressed in rodent muscle during regeneration, in human fetal muscle and in myopathies, with localization to both satellite cells and myotubes [11] Together, these data suggest that Dlk is likely to be involved in myogenesis/growth of skeletal muscle during normal embryonic development with expression possibly recapitulated in regenerating muscle. Considering that maturation arrest is proposed as a factor in the development of rhabdomyosarcomas (RMS) [14] this study was designed to elucidate if skeletal muscle neoplasias express Dlk, and further, to determine if Dlk in muscle influences myogenesis
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