Serum response factor (SRF) regulates transcription of numerous muscle and growth factor-inducible genes. Because SRF is not muscle specific, it has been postulated to activate muscle genes by recruiting myogenic accessory factors. Using a bioinformatics-based screen for unknown cardiac-specific genes, we identified a novel and highly potent transcription factor, named myocardin, that is expressed in cardiac and smooth muscle cells. Myocardin belongs to the SAP domain family of nuclear proteins and activates cardiac muscle promoters by associating with SRF. Expression of a dominant negative mutant of myocardin in Xenopus embryos interferes with myocardial cell differentiation. Myocardin is the founding member of a class of muscle transcription factors and provides a mechanism whereby SRF can convey myogenic activity to cardiac muscle genes.

Members of the MyoD family of basic helix-loop-helix (bHLH) transcription factors control the formation of all skeletal muscles in vertebrates, but little is known of the molecules or mechanisms that confer unique identities to different types of skeletal muscles. MyoR and capsulin are related bHLH transcription factors expressed in specific facial muscle precursors. We show that specific facial muscles are missing in mice lacking both MyoR and capsulin, reflecting the absence of MyoD family gene expression and ablation of the corresponding myogenic lineages. These findings identify MyoR and capsulin as unique transcription factors for the development of specific head muscles.

Formation of numerous internal organs involves reciprocal epithelial-mesenchymal signaling and subsequent patterning and growth of the organ primordium. Capsulin is a basic helix-loophelix transcription factor expressed in mesenchymal cells that encapsulate the epithelial primordia of internal organs, including the kidney and lung, as well as the epicardium, which gives rise to the coronary arteries. Capsulin is also expressed in the mesothelium that gives rise to the spleen. We demonstrate that mice homozygous for a capsulin null mutation fail to form a spleen. The homeobox genes Hox11 and Bapx1, shown previously to be essential regulators of spleen organogenesis, and a lacZ reporter introduced into the capsulin locus, were expressed in the early splenic primordium, derived from the splanchnic mesoderm, of homozygous mutant embryos. However, this primordium failed to develop beyond an initial group of precursor cells and underwent rapid apoptosis. The phenotype of capsulin mutant mice demonstrates that capsulin acts within a subpopulation of splanchnic mesodermal cells to control an essential early step in spleen organogenesis that is likely to represent a point of regulatory convergence of the capsulin, Hox11, and Bapx1 genes.

Serum response factor (SRF) is a MADS box transcription factor that regulates muscle-specific and growth factor-inducible genes by binding the consensus sequence CC(A/T) 6 GG, known as a CArG box. Because SRF expression is not restricted solely to muscle, its expression alone cannot account for the muscle specificity of some of its target genes. To understand further the role of SRF in muscle-specific transcription, we created transgenic mice harboring lacZ transgenes linked to tandem copies of different CArG boxes with flanking sequences. CArG boxes from the SM22 and skeletal ␣-actin promoters directed highly restricted expression in developing smooth, cardiac, and skeletal muscle cells during early embryogenesis. In contrast, the CArG box and flanking sequences from the c-fos promoter directed expression throughout the embryo, with no preference for muscle cells. Systematic swapping of the core and flanking sequences of the SM22 and c-fos CArG boxes revealed that cell type specificity was dictated in large part by sequences immediately flanking the CArG box core. Sequences that directed widespread embryonic expression bound SRF more strongly than those that directed muscle-restricted expression. We conclude that sequence variations among CArG boxes influence cell type specificity of expression and account, at least in part, for the ability of SRF to distinguish between growth factor-inducible and muscle-specific genes in vivo.

The patient was a 60-year-old woman who felt well until she developed fatigue and cervical lymphadenopathy. Her WBC count was found to be elevated at 27,500/mm 3 with a differential of 17% neutrophils, 44% lymphocytes, 5% atypical lymphocytes, and 30% atypical mononuclear cells with prominent nucleoli and cytoplasmic blebs; hematocrit was 45.6% and platelet count was 208,000/ mm 3 . A previous CBC from 4 months earlier was normal. Flow cytometry of the peripheral blood demonstrated a predominant population of T cells positive for CD2, CD3, CD4, CD5, and CD7, and negative for CD8, suspicious for T-cell lymphoma. A bone marrow aspiration and biopsy showed a moderately hypercellular marrow with aggregates of atypical small to medium-sized lymphocytes comprising approximately 30% of the overall cellularity (Figs 1A and 1B). Immunohistochemistry of the core biopsy revealed the lymphocytes to be CD3ϩ T cells (Fig 1C) that overwhelmingly coexpressed CD4 (Fig 1D), but not CD8 (Fig 1D inset), an identical immunophenotype to that seen by flow cytometry of the peripheral blood. In situ hybridization with an Epstein-Barr virus (EBV)-encoded RNA probe was negative. Fluorescent in situ hybridization analysis identified del(11q) in 104 of 125 nuclei. The patient was diagnosed with T-cell prolymphocytic leukemia (T-PLL). 1