Self-Organized Shuttling: Generating Sharp Dorsoventral Polarity in the Early Drosophila Embryo

Abstract

Morphogen gradients pattern tissues and organs during development. When morphogen production is spatially restricted, diffusion and degradation are sufficient to generate sharp concentration gradients. It is less clear how sharp gradients can arise within the source of a broadly expressed morphogen. A recent solution relies on localized production of an inhibitor outside the domain of morphogen production, which effectively redistributes (shuttles) and concentrates the morphogen within its expression domain. Here, we study how a sharp gradient is established without a localized inhibitor, focusing on early dorsoventral patterning of the Drosophila embryo, where an active ligand and its inhibitor are concomitantly generated in a broad ventral domain. Using theory and experiments, we show that a sharp Toll activation gradient is produced through "self-organized shuttling," which dynamically relocalizes inhibitor production to lateral regions, followed by inhibitor-dependent ventral shuttling of the activating ligand Spätzle. Shuttling may represent a general paradigm for patterning early embryos.

Morphogen transport

“…Shuttling is a special case of facilitated diffusion, in which the 'shuttles', not the morphogens, are generated from a localized source (Holley et al, 1996;Eldar et al, 2002;Mizutani et al, 2005;Shimmi et al, 2005;van der Zee et al, 2006;Ben-Zvi et al, 2008;Wang et al, 2008;Ben-Zvi et al, 2011;Haskel-Ittah et al, 2012;Matsuda and Shimmi, 2012;Sawala et al, 2012). The association of morphogen molecules with shuttles results in the formation of a morphogen gradient from an initially broad or even uniform morphogen distribution (Fig.…”

“…Second, it has been proposed that the posttranslational modifications and hydrophobicity of morphogens prevent their diffusion in aqueous environments. However, multiple mechanisms have been identified that serve to solubilize morphogens (reviewed by Müller and Schier, 2011;Creanga et al, 2012;Haskel-Ittah et al, 2012;Mulligan et al, 2012;Sawala et al, 2012;Tukachinsky et al, 2012). Third, it has been argued that morphogen gradients "must be constructed with a high degree of reliability; yet it is unlikely that a substance freely diffusible in the extracellular space could provide a very reproducible long-range distribution" (Kerszberg and Wolpert, 1998).…”

“…Intriguingly, Lefty has a much longer range than Nodal, even though both molecules are TGFβ superfamily members and expressed in zebrafish embryos. The Thiele modulus (a dimensionless number; φ=L ͱ k/D --, where D is the diffusion coefficient, k is the clearance rate constant, and L the length of the field) is a measure of the relative range of a signaling molecule with respect to the length of the patterning field, assuming that the gradient is generated by localized production, diffusion and uniform clearance (Thiele, 1939;Goentoro et al, 2006;Reeves and Stathopoulos, 2009;Haskel-Ittah et al, 2012). The Thiele modulus thus defines the term 'gradient range' and allows for comparison of ranges in differently sized patterning fields (e.g.…”

Studies of morphogens: keep calm and carry on

“…Benny Shilo (Weizmann Institute of Science, Israel) presented a shuttling mechanism for the extracellular protein Spätzle (Spz), a ligand for the Toll receptor, which acts to shape dorsalventral patterning in the Drosophila embryo. Distinct roles of N-and C-terminal fragments of Spz as inhibitor and activator, respectively, coupled with their capacity to associate with each other in multiple forms, leads to dynamic relocalization of these protein segments to support formation and sharpening of the Toll activation gradient (Haskel-Ittah et al, 2012).…”

Spatiotemporal Analysis of Different Mechanisms for Interpreting Morphogen Gradients

“…The formation and shape of a morphogen gradient is influenced by many factors, such as how the morphogen is produced (36,37), how it is degraded (38,39), how it is transported (23,(40)(41)(42)(43), and how it interacts with other system components (44). The original and conceptually simplest morphogen model involves a single morphogen species that diffuses freely, degrades at constant rate, and is produced/injected at one end of the system (23).…”