Lepidopteran DALP, and its mammalian ortholog HIC-5, function as negative regulators of muscle differentiation.
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.
Hu
Y
Y
Molecular and Cellular Biology Program, University of Massachusetts, Amherst, MA 01003, USA.
Cascone
P J
PJ
Cheng
L
L
Sun
D
D
Nambu
J R
JR
Schwartz
L M
LM
D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D002454:Cell Differentiation; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D004330:Drosophila; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D019476:Insect Proteins; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D008322:Mammals; D018402:Manduca / Q000235:genetics / Q000254:growth & development*; D051379:Mice; D008969:Molecular Sequence Data; D024510:Muscle Development; D009132:Muscles / Q000166:cytology; D011994:Recombinant Proteins / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D016335:Zinc Fingers
D003598:Cytoskeletal Proteins; C121526:DALP protein, Manduca sexta; D004268:DNA-Binding Proteins; D019476:Insect Proteins; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D011994:Recombinant Proteins; C490351:TGFB1I1 protein, human; C090090:Tgfb1i1 protein, mouse; D014157:Transcription Factors