S Zaffran X Xt PCH Lo HH Lee and M Frasch

Brookdale Department of Molecular, Cell, and Developmental Biology, Mount Sinai School of Medicine,

New York, New York 10029

The dorsal vessel of Drosophila displays developmental, functional, and morphological similarities to the primitive linear heart tube of early vertebrate embryos. Because these similarities extend to the genetic and molecular level, Drosophila has become a fruitful model to study control mechanisms of early heart development. Herein we summarize recently obtained insights into control mechanisms during early induction and diversification of cardiac progenitors in Drosophila. We also show that induction of tinman, a key cardiogenic gene, in the dorsal mesoderm by Dpp (Drosophila BMP) involves protein/protein interactions between Tinman and the Smad proteins Mad and Medea, in addition to their DNA-binding activities to specific tinman enhancer sequences. Furthermore, we present evidence that binding of a high-mobility-group protein, HMG-D, to the Dpp-responsive enhancer of tinman as well as to the Tinman protein may be involved in the formation of a fully active enhancer complex.

MORPHOLOGY AND PATTERNING OF THE DORSAL VESSEL

The dorsal vessel consists of a linear tube extending along the dorsal midline of the Drosophila larva (Fig. 1A) and late-stage embryo (Fig. 1B). This organ is composed of an inner tube formed by contractile cardiomyocytes (termed cardioblasts; Fig. 1A,B) that are surrounded by non-contractile pericardial cells (Fig. 1C,D). In late-stage embryos, the cardiomyocytes are arranged in two bilateral rows of cells that enclose the lumen of the dorsal vessel (Fig. 1B) (Rugendorff et al. 1994). Peripheral components of the dorsal vessel include the segmentally arranged alary muscles, which attach the dorsal vessel to the body wall (Fig. 1A). Like the vertebrate heart tube, the Drosophila dorsal vessel has an anterior/posterior polarity and pumps the hemolymph from posterior to anterior. This polarity is also reflected in the subdivision of the dorsal vessel into two chamber-like portions, an ante-

Present addresses: *Department de Biologie du Développement, Institut Pasteur, 75015 Paris, France; "^Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02120.

rior one with a narrower lumen, termed "aorta," and a posterior one with a wider diameter, termed "heart" (Fig. 1A,B). In addition, the heart portion features larger alary muscles (Fig. 1A) and three bilateral pairs of inflow tracts, termed "ostia" (Fig. 1B). Although more simple, this type of anteroposterior subdivision is reminiscent of the anteroposterior subdivision of the linear vertebrate heart tube into presumptive heart chambers.

In addition to the broad anteroposterior polarity, the dorsal vessel also displays an intrasegmental polarity along its anteroposterior extent. Indeed, expression analysis of various molecular markers has revealed that, analogous to the remainder of the insect body, the dorsal vessel is composed of segmentally repeated units. For example, the NK homeobox gene tinman (tin), which has an essential early function in cardiogenesis (see below), is expressed in only four of the six bilateral cardioblasts in each segment of the mature dorsal vessel (Fig. 1B-E). On the basis of the differential expression of the sulfonylurea receptor (a potassium channel subunit; Fig. 1E) as well as other differentiation markers, it appears that these four cardioblasts acquire different physiological characteristics from the two tin-negative cells. The specific expression of the homeobox gene ladybird (lb) in two bilateral, anterior pairs of tin-positive cardioblasts within each segment provides an additional level of diversity among these cardioblasts (Jagla et al. 1997). Similarly, the tinnegative pair of cardioblasts in each hemisegment is characterized by the expression of other transcription factors. Notably, these include seven-up (svp; Fig. 1C), which encodes a nuclear orphan receptor that is homologous to vertebrate COUP-TF, and the three related Dorsocross genes (Doc1 aka Tb66F2, Doc2, Doc3; Fig. 1D) that are closest to the Tbx4, 5, and 6 subgroup of vertebrate T-box genes. In the "heart" portion of the dorsal vessel, the tin-negative/svp- and Doc-positive cells form the ostia (inflow tracts), demonstrating that the intrasegmental diversification of cardioblasts leads to physiological as well as functional and morphological differences among these cells (Fig. 1B) (Molina and Cripps 2001).

Genetic studies have uncovered some of the mechanisms that control intrasegmental cell fate diversification within the dorsal vessel (Gajewski et al. 2000; Lo and Frasch 2001). Specifically, it has been shown that svp acts as an upstream regulator to repress tin and activate Doc in two of the six bilateral cardioblasts in each segment (Fig.

Cold Spring Harbor Symposia on Quantitative Biology, Volume LXVII. © 2002 Cold Spring Harbor Laboratory Press 0-87969-678-8/02.

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