Control of a genetic regulatory network by a selector gene.

The formation of many complex structures is controlled by a special class of transcription factors encoded by selector genes. It is shown that SCALLOPED, the DNA binding component of the selector protein complex for the Drosophila wing field, binds to and directly regulates the cis-regulatory elements of many individual target genes within the genetic regulatory network controlling wing development. Furthermore, combinations of binding sites for SCALLOPED and transcriptional effectors of signaling pathways are necessary and sufficient to specify wing-specific responses to different signaling pathways. The obligate integration of selector and signaling protein inputs on cis-regulatory DNA may be a general mechanism by which selector proteins control extensive genetic regulatory networks during development.

The Vestigial and Scalloped proteins act together to directly regulate wing-specific gene expression in Drosophila.

A small number of major regulatory (selector) genes have been identified in animals that control the development of particular organs or complex structures. In Drosophila, the vestigial gene is required for wing formation and is able to induce wing-like outgrowths on other structures. However, the molecular function of the nuclear Vestigial protein, which bears no informative similarities to other proteins, was unknown. Here, we show that Vestigial requires the function of the Scalloped protein, a member of the TEA family of transcriptional regulators, to directly activate the expression of genes involved in wing morphogenesis. Genetic and molecular analyses reveal that Vestigial regulates wing identity by forming a complex with the Scalloped protein that binds sequence specifically to essential sites in wing-specific enhancers. These enhancers also require the direct inputs of signaling pathways, and the response of an enhancer can be switched to another pathway through changes in signal-transducer binding sites. Combinatorial regulation by selector proteins and signal transducers is likely to be a general feature of the tissue-specific control of gene expression during organogenesis.

Integration of positional signals and regulation of wing formation and identity by Drosophila vestigial gene.

Appendage formation is organized by signals from discrete sources that presumably act upon downstream genes to control growth and patterning. The Drosophila vestigial gene is selectively required for wing-cell proliferation, and is sufficient to induce outgrowths of wing tissue from eyes, legs and antennae. Different signals activate separate enhancers to control vestigial expression: first, in the dorsal/ventral organizer through the Notch pathway, and subsequently, in the developing wing blade by decapentaplegic and a signal from the dorsal/ventral organizer. Signal integration must be a general feature of genes like vestigial, that regulate growth or patterning along more than one axis.

The concentration of B52, an essential splicing factor and regulator of splice site choice in vitro, is critical for Drosophila development.

B52 is a Drosophila melanogaster protein that plays a role in general and alternative splicing in vitro. It is homologous to the human splicing factor ASF/SF2 which is essential for an early step(s) in spliceosome assembly in vitro and also regulates 5' and 3' alternative splice site choice in a concentration-dependent manner. In vitro, B52 can function as both a general splicing factor and a regulator of 5' alternative splice site choice. Its activity in vivo, however, is largely uncharacterized. In this study, we have further characterized B52 in vivo. Using Western blot (immunoblot) analysis and whole-mount immunofluorescence, we demonstrate that B52 is widely expressed throughout development, although some developmental stages and tissues appear to have higher B52 levels than others do. In particular, B52 accumulates in ovaries, where it is packaged into the developing egg and is localized to nuclei by the late blastoderm stage of embryonic development. We also overexpressed this protein in transgenic flies in a variety of developmental and tissue-specific patterns to examine the effects of altering the concentration of this splicing factor in vivo. We show that, in many cell types, changing the concentration of B52 adversely affects the development of the organism. We discuss the significance of these observations with regard to previous in vitro results.

Infectious mononucleosis and fatal myocarditis.

Mycocarditis is an uncommon manifestation and, very rarely, a lethal complication of infectious mononucleosis. A 14-year-old girl initially had exudative pharyngitis and splenomegaly and developed refractory ventricular fibrillation. The diagnosis of infectious mononucleosis was confirmed by both a strongly positive heterophil antibody test and a high titer of Epstein-Barr virus. Pathologic studies demonstrated extensive histiocytic and lypmhocytic infiltration of the myocardium.

Effect of exercise on left ventricular ejection time in patients with prolapsing mitral leaflet syndrome.

The effect of exercise on left ventricular ejection time was determined in 12 subjects with prolapsing mitral valve leaflet syndrome (PML). A single lead ECG (CM5), phonocardiogram and carotid pulse contour were recorded simultaneously with the subjects at supine rest before and immediately after multistage treadmill exercise. Systolic time intervals were measured from five consecutive complexes to determine the pre-ejection period (PEP), left ventricular ejection time (LVET) and total electromechanical systole (QS2). LVET was corrected for heart rate and defines as LVETc. In nine subjects, an increase of 1 to 49 msec was observed in the LVETc following exercise. A shorter resting LVETc and greater afterload at peak exercise was related to an increase in LVETc of 10 msec or more. Exercise elicited or evoked evidence of left ventricular dysfunction. The results support the concept that impaired left ventricular performance is a concomitant of this syndrome.