Ligand Integration and Receptor Synergy

Decapentaplegic (Dpp), the fly ortholog of human BMP2/4, acts as a morphogen in the early embryo to specify dorsal cell fates. We have previously shown that a second ligand, the BMP7 homolog Screw (Scw) is also essential for dorsal embryonic development, and has the intriguing ability to potentiate Dpp signaling (Arora et al., 1994). Cooperation between these two BMP pathways results in high levels of signaling that are crucial for establishment of the entire range of dorsal cell fates. Interestingly, the embryo is acutely sensitive to different doses of Dpp activity, even in the absence of Scw, but is insensitive to Scw unless Dpp is present. Thus the only function of Scw is to “boost” Dpp signaling.

Dpp and Scw act through different receptors - Tkv mediates the response to Dpp, while Sax is required for Scw signaling. Ligand independent, constitutively active forms of Sax and Tkv also induce a stronger signal when coinjected into naïve embryos, suggesting that the synergy between the two pathways occurs post-receptor activation (Letsou et al., 1995; Nguyen et al., 1998). We are interested in understanding the mechanistic basis of receptor synergy and have used an extensive structure-function analysis to identify domains in the receptor that regulate its function, potency and ability to synergize. We are addressing this question both in cultured cells as well as in vivo, using whole embryo analysis.

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