title: Formation of the long range Dpp morphogen gradient.
abstract: The TGF-β homolog Decapentaplegic (Dpp) acts as a secreted morphogen in the Drosophila wing disc, and spreads through the target tissue in order to form a long range concentration gradient. Despite extensive studies, the mechanism by which the Dpp gradient is formed remains controversial. Two opposing mechanisms have been proposed: receptor-mediated transcytosis (RMT) and restricted extracellular diffusion (RED). In these scenarios the receptor for Dpp plays different roles. In the RMT model it is essential for endocytosis, re-secretion, and thus transport of Dpp, whereas in the RED model it merely modulates Dpp distribution by binding it at the cell surface for internalization and subsequent degradation. Here we analyzed the effect of receptor mutant clones on the Dpp profile in quantitative mathematical models representing transport by either RMT or RED. We then, using novel genetic tools, experimentally monitored the actual Dpp gradient in wing discs containing receptor gain-of-function and loss-of-function clones. Gain-of-function clones reveal that Dpp binds in vivo strongly to the type I receptor Thick veins, but not to the type II receptor Punt. Importantly, results with the loss-of-function clones then refute the RMT model for Dpp gradient formation, while supporting the RED model in which the majority of Dpp is not bound to Thick veins. Together our results show that receptor-mediated transcytosis cannot account for Dpp gradient formation, and support restricted extracellular diffusion as the main mechanism for Dpp dispersal. The properties of this mechanism, in which only a minority of Dpp is receptor-bound, may facilitate long-range distribution.
authors.affiliation: Institute of Molecular Life Sciences, University of Zurich, Switzerland.
authors.forename: Gerald
authors.initials: G
authors.lastname: Schwank
authors.forename: Sascha
authors.initials: S
authors.lastname: Dalessi
authors.forename: Schu-Fee
authors.initials: SF
authors.lastname: Yang
authors.forename: Ryohei
authors.initials: R
authors.lastname: Yagi
authors.forename: Aitana Morton
authors.initials: AM
authors.lastname: de Lachapelle
authors.forename: Markus
authors.initials: M
authors.lastname: Affolter
authors.forename: Sven
authors.initials: S
authors.lastname: Bergmann
authors.forename: Konrad
authors.initials: K
authors.lastname: Basler
mesh_terms: D030301:Activin Receptors, Type II / Q000235:genetics / Q000378:metabolism; D000465:Algorithms; D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000033:anatomy & histology / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D007814:Larva / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D008956:Models, Chemical; D009024:Morphogenesis; D009154:Mutation; D009928:Organ Specificity; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D014921:Wings, Animal / Q000254:growth & development / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D011956:Receptors, Cell Surface; C064196:dpp protein, Drosophila; C090169:tkv protein, Drosophila; D017346:Protein Serine-Threonine Kinases; D030301:Activin Receptors, Type II; C425583:put protein, Drosophila