Mechanisms of Morphogen Gradient Formation
One essential issue in developmental biology is how cells in a developing field acquire their positional information to determine their fates. The concept of morphogen provides part of explanation for this important process. Secreted morphogens emanate from localized sources to form gradients that differentially regulate cell fates in a concentration-dependent manner. The problem of how morphogen gradients arise in tissues has attracted intensive studies in recent years. However, the molecular mechanisms of morphogen transport are still unclear.
Drosophila wing imaginal disc has provided a paradigm to dissect the mechanisms of morphogen gradient formation and its interpretation. The development of wing disc is controlled by three secreted morphogens including (1) Wingless (Wg), a member of Wnt family; (2) Decapentaplegic (Dpp), a member of BMP family, and (3) Hh. While Wg is required for D/V patterning, Hh and Dpp control the patterning of A/P axis.
We have demonstrated that Heparan sulfate proteoglycans (HSPGs) are essential for establishing the extracellular gradients of Wg, Dpp and Hh. We further demonstrated that Dally and Dally-like (Dlp), two Drosophila glypican members of HSPGs are involved. Both Dally and Dlp are expressed in unique regions of wing discs and control the distributions and signaling activity of all three morphogen molecules.
Using Drosophila wing disc as a model, we have addressed the mechanisms of morphogen transport. Our results showed that all three morphogens (Dpp, Hh and Wg) are mainly transported by extracellular diffusion mechanisms involving both Dally and Dlp. Dynamin-mediated endocytosis is required for receptor-mediated ligand degradation, but is not essential for morphogen transport.
Current experiments are focused on determining the respective roles of HSPGs, lipid modifications and receptor-mediated endocytosis on Wg, Hh and Dpp distributions.
