Abstract
Expression of many skeletal muscle-specific genes depends on TEF-1 (transcription enhancer factor-1) and MEF2 transcription factors. In Drosophila, the TEF-1 homolog Scalloped interacts with the cofactor Vestigial to drive differentiation of the wing and indirect flight muscles. Here, we identify three mammalian vestigial-like genes, Vgl-1, Vgl-2, and Vgl-3, that share homology in a TEF-1 interaction domain. Vgl-1 and Vgl-3 transcripts are enriched in the placenta, whereas Vgl-2 is expressed in the differentiating somites and branchial arches during embryogenesis and is skeletal muscle-specific in the adult. During muscle differentiation, Vgl-2 mRNA levels increase and Vgl-2 protein translocates from the cytoplasm to the nucleus. In situ hybridization revealed co-expression of Vgl-2 with myogenin in the differentiating muscle of embryonic myotomes but not in newly formed somites prior to muscle differentiation. Like Vgl-1, Vgl-2 interacts with TEF-1. In addition, we show that Vgl-2 interacts with MEF2 in a mammalian two-hybrid assay and that Vgl-2 selectively binds to MEF2 in vitro. Co-expression of Vgl-2 with MEF2 markedly co-activates an MEF2-dependent promoter through its MEF2 element. Overexpression of Vgl-2 in MyoD-transfected 10T(1/2) cells markedly increased myosin heavy chain expression, a marker of terminal muscle differentiation. These results identify Vgl-2 as an important new component of the myogenic program.
Highlights
Commitment of pluripotent cells to the skeletal muscle lineage involves multiple inductive signals and the hierarchical activation of several transcription factors [1]
Northern blot analysis of fetal tissues revealed tondu mRNA in fetal kidney and lung, expression was not examined in adult tissues. tondu was shown to physically and functionally interact with transcription enhancer factor-1 (TEF-1). We identified this cDNA in a search of the GenBankTM data base for genes related to Drosophila vestigial, but gave it the name Vestigial-like 1 (Vgl-1), based on its homology to the previously described Drosophila vestigial
One on Xq26.1–27.2, one on 6q21, and a third on chromosome 3, contained a sequence motif related to the TEF-1 interaction domain of Vestigial
Summary
Commitment of pluripotent cells to the skeletal muscle lineage involves multiple inductive signals and the hierarchical activation of several transcription factors [1]. Proteins that interact with TEF-1 include the basic-helix-loop-helix leucine zipper protein Max [10], the nuclear protein poly(ADP-ribose)polymerase [9], the steroid receptor co-activator proteins [11], the Src/Yes-associated protein YAP65 [12], and a serum response factor [13]. Some of these cofactors are known to participate in muscle differentiation. Binding of the Vestigial cofactor switches the DNA-target selectivity of the Scalloped protein [21] and activates wing-specific genes. Binding of the Vestigial cofactor switches the DNA-target selectivity of the Scalloped protein [21] and activates wing-specific genes. vestigial expression is regulated by inputs from three signaling pathways: Wingless, Decapentaplegic, and Notch/Suppressor of Hairless and by its own
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