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A Drosophila homolog of the serine/threonine kinase GSK-3??, encoded by the zest-white3/shaggy gene (zw3), has been implicated as a maternally provided antagonist of zygotic signaling by the secreted segmentation gene wingless (wg). The wg signal apparently causes a spatially localized inhibition of the ubiquitous repressor function of zw3. This double negative mechanism of signal transduction has been shown to mediate the patterning function of Wg in a number of developmental processes. Although wg is absolutely required for specifying the heart progenitors within the mesoderm of Drosophila, the role of zw3 in this process has been unclear. Here, we present evidence that zw3 has a dual role in mesoderm development: (1) zw3 acts as an antagonist in cardiogenic wg signal transduction, and (2) zw3 also seems to be required to promote positively the formation of a larger mesodermal region, the tinman - and dpp -dependent???dorsal mesoderm,??? which is a prerequisite not only for cardiogenesis, but also for visceral mesoderm formation. We also demonstrate that a recently identified proximal component of the wg cascade, which is a transcription factor encoded by pangolin/dTCF (dTCF), also seems to mediate wg -dependent cardiogenesis. Further, we present evidence that Notch (N), which opposes wg signaling in other situations, is unlikely to be directly involved in the cardiogenic wg pathway, but seems to have multiple other myogenic functions, one of which is to inhibit mesoderm differentiation altogether, when overexpressed as a constitutively active form. Dev. Genet. 22:201???211, 1998.?? 1998 Wiley-Liss, Inc.