BMPs, the largest family of secreted signaling molecules within the TGF-beta super-family, regulate many processes critical for organismal development, as well as tissue repair. Many components of the TGF-a and BMP signaling pathways are directly implicated in a number of human diseases, most notably heritable neoplastic vascular disorders and gastrointestinal neoplasias. As morphogens, many BMPs are capable of eliciting diverse cellular responses, thought to be determined by the level of signaling. Interestingly, several human disorders and syndromes have recently been attributed to abnormal levels of signaling by BMPs or TGF-betas. In studies of development, the morphogen gradient theory has been useful in guiding research aimed at understanding how positional information and the specification of multiple cell fates are achieved. Despite our extensive knowledge of which molecules are important in patterning, such as BMPs, our understanding of how gradients of morphogenetic information are generated and interpreted is surprisingly limited. Data from our laboratory shows that the BMP activity gradient responsible for patterning the Drosophila wing is generated by the differential contribution of two BMPs, Gbb and Dpp. Dpp exhibits short range signaling activity to pattern cell fates near its source in the central domain of the wing imaginal disc, while Gbb exhibits long range signaling activity to pattern elements found far from its source. The experiments outlined in this proposal are aimed at identifying the molecular basis of this difference in range of signaling.
Our aims are:
Aim 1 : Identify the protein domains of BMP ligands important in determining functional range;
Aim 2 : Identify sequences and processes critical for regulating functional range;
and Aim 3 : Elucidate the relationship between physical range and functional range. The unique strength of the proposed structure/function analysis is that function will be assayed in vivo, at endogenous levels, in the normal context of the developing organ. Such an analysis is essential for furthering our understanding of BMP signaling, given the extreme sensitivity of cells to the level of signaling output from this pathway. The role of the BMP type I receptors in generating the BMP activity gradient will be determined, as will the effect of BMP ligand co-expression. Results from these experiments will have a significant impact on our understanding of how BMP signaling levels are regulated.
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