Receptor binding and tissue architecture explain the morphogen local-to-global mobility transition

Abstract

Morphogens are intercellular signaling molecules providing spatial information to cells in developing tissues to coordinate cell fate decisions. The spatial information is encoded within long-ranged concentration gradients of the morphogen. Direct measurement of morphogen dynamics in a range of systems suggests that local and global diffusion coefficients can differ by orders of magnitude. Further, local diffusivity can be large, which would potentially abolish any concentration gradient rapidly. Such observations have led to alternative transport models being proposed, including transcytosis and cytonemes. Here, we show that accounting for tissue architecture combined with receptor binding is sufficient to hinder the diffusive dynamics of morphogens, leading to an order of magnitude decrease in the effective diffusion coefficient from local to global scales. In particular, we built a realistic in silico architecture of the extracellular spaces of the zebrafish brain using light and electron microscopy data. Simulations on realistic architectures demonstrate that tortuosity and receptor binding within these spaces are sufficient to reproduce experimentally measured morphogen dynamics. Importantly, this work demonstrates that hindered diffusion is a viable mechanism for gradient formation, without requiring additional regulatory control.

Morphogen gradients are regulated by porous media characteristics of the developing tissue

“…Limited by the light diffraction limit and segmentation errors, our geometry model likely overestimated the thickness of ECS structures due to light. We, therefore, expect the real τ d to be even larger [135].…”

“…When circumventing obstacles in tortuous porous media, molecules have to move further on average to reach the same mean square displacement as in free space, leading to reduced effective diffusivity [10, 14, 18, 20, 30, 39, 83, 106, 112]. Moreover, some parts of a porous medium may be inaccessible due to imperfect pore connectivity, i.e., dead-ends [53, 135], compartmentalizing the space.…”

“…The porous ECS geometry can, therefore, be expected to significantly influence extracellular morphogen transport [106, 135]. The effective morphogen-receptor binding rate can be significantly smaller than the intrinsic rate and depend on the effective diffusivity [96, 126].…”

“…The effective morphogen-receptor binding rate can be significantly smaller than the intrinsic rate and depend on the effective diffusivity [96, 126]. Diffusive hindrance, domain compartmentalization, and receptor localization hence influence morphogen gradient formation and maintenance in porous ECS geometries [70, 83, 120, 134, 135].…”