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Lepidopteran DALP, and its mammalian ortholog HIC-5, function as negative regulators of muscle differentiation

1999; National Academy of Sciences; Volume: 96; Issue: 18 Linguagem: Inglês

10.1073/pnas.96.18.10218

1091-6490

Yanhui Hu, Pamela J. Cascone, Lihong Cheng, Danhui Sun, John R. Nambu, Lawrence M. Schwartz,

Signaling Pathways in Disease

During myogenesis, reductions in trophic factor availability signal most myoblasts to fuse, up-regulate the expression of muscle-specific genes, and form myotubes. Those cells failing to differentiate into myotubes initiate apoptosis and rapidly die. At present, the signal-transduction molecules that determine whether myoblasts should differentiate or die are largely unknown. In this report, we describe the cloning and characterization of DALP , a small LIM-only type zinc-finger protein that is induced when the intersegmental muscles (ISMs) of the moth Manduca sexta become committed to die at the end of metamorphosis. Forced expression of death-associated LIM-only protein (DALP) in Drosophila results in skeletal muscle atrophy. Ectopic expression of DALP, or its mammalian ortholog Hic-5, blocks differentiation and induces apoptosis in mouse C 2 C 12 myoblasts. Both of these effects can be overcome by contact with normal myoblasts or by ectopic expression of the muscle-specific transcription factor MyoD. Hic-5 expression is specifically and dramatically induced in normal myoblasts that die after removal of trophic support. Taken together, these data suggest that DALP and Hic-5 act upstream of MyoD and function as phylogenetically conserved “switches” to block muscle differentiation and induce death.