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Title

Morphogenetic action through flux-limited spreading

AuthorsVerbeni, Michela; Sánchez, Óscar; Mollica, Emanuela ; Siegl-Cachedenier, I.; Carleton, A.; Guerrero Vega, Isabel ; Ruiz i Altaba, Ariel; Soler, Juan
KeywordsFlux-limited
Filopodia-likestructures
Hedgehog
Morphogeneticgradients
Issue Date2013
PublisherElsevier
CitationPhysics of Life Reviews 10: 457- 475 (2013)
AbstractA central question in biology is how secreted morphogens act to induce different cellular responses within a group of cells in a concentration-dependent manner. Modeling morphogenetic output in multicellular systems has so far employed linear diffusion, which is the normal type of diffusion associated with Brownian processes. However, there is evidence that at least some morphogens, such as Hedgehog (Hh) molecules, may not freely diffuse. Moreover, the mathematical analysis of such models necessarily implies unrealistic instantaneous spreading of morphogen molecules, which are derived from the assumptions of Brownian motion in its continuous formulation. A strict mathematical model considering Fick's diffusion law predicts morphogen exposure of the whole tissue at the same time. Such a strict model thus does not describe true biological patterns, even if similar and attractive patterns appear as results of applying such simple model. To eliminate non-biological behaviors from diffusion models we introduce flux-limited spreading (FLS), which implies a restricted velocity for morphogen propagation and a nonlinear mechanism of transport. Using FLS and focusing on intercellular Hh-Gli signaling, we model a morphogen gradient and highlight the propagation velocity of morphogen particles as a new key biological parameter. This model is then applied to the formation and action of the Sonic Hh (Shh) gradient in the vertebrate embryonic neural tube using our experimental data on Hh spreading in heterologous systems together with published data. Unlike linear diffusion models, FLS modeling predicts concentration fronts and the evolution of gradient dynamics and responses over time. In addition to spreading restrictions by extracellular binding partners, we suggest that the constraints imposed by direct bridges of information transfer such as nanotubes or cytonemes underlie FLS. Indeed, we detect and measure morphogen particle velocity in such cell extensions in different systems. © 2013 Elsevier B.V.
URIhttp://hdl.handle.net/10261/98060
DOI10.1016/j.plrev.2013.06.004
Identifiersdoi: 10.1016/j.plrev.2013.06.004
issn: 1571-0645
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