New Model for Understanding Mechanisms of Biological Signaling: Direct Transport via Cytonemes

Abstract

Biological signaling is a crucial natural process that governs the formation of all multicellular organisms. It relies on efficient and fast transfer of information between different cells and tissues. It has been presumed for a long time that these long-distance communications in most systems can take place only indirectly via the diffusion of signaling molecules, also known as morphogens, through the extracellular fluid. However, recent experiments indicate that there is also an alternative direct delivery mechanism. It utilizes dynamic tubular cellular extensions, called cytonemes, that directly connect cells, supporting the flux of morphogens to specific locations. We present a first quantitative analysis of the cytoneme-mediated mechanism of biological signaling. Dynamics of the formation of signaling molecule profiles, which are also known as morphogen gradients, is discussed. It is found that the direct-delivery mechanism is more robust with respect to fluctuations in comparison with the passive diffusion mechanism. In addition, we show that the direct transport of morphogens through cytonemes

Bidirectional transport model of morphogen gradient formation via cytonemes

“…Our analysis strongly suggests that in order to ensure that the morphogen gradient is not exponentially sensitive to fluctuations in the production rate, it is necessary that v < 0. This reinforces the observation of [33] that robustness comes at the expense of an energy cost, in this case a strong retrograde flow.…”

“…In this paper, we considered a simple bidirectional motor transport model for the flux of morphogens along a set of cytonemes, which link a source cell to a one-dimensional array of target cells. We obtained an analytical steady-state solution of the transport equations, which enabled us to identify the phenomenological transport rate of [33] with a biophysically derived expression. In particular, we related the energy cost of cytoneme-based morphogenesis with the degree of retrograde transport.…”

“…Hence, a continuously varying morphogen concentration can be converted into a discrete spatial pattern of differentiated gene expression across a cell population. The most common mechanism of morphogen gradient formation is thought to involve a localized source of protein production within the embryo, combined with diffusion away from the source and subsequent degradation [1,22,24,31,33,36]. The latter can arise either from degradation within the extracellular domain or by binding to membrane bound receptors and subsequent removal from the diffusing pool by endocytosis (see figure 1(b)).…”

Mechanisms of the formation of biological signaling profiles

“…This model can be solved by analyzing the single-molecule probability density function P n (t) of finding the morphogen at the site n at time t. The temporal evolution of this probability function follows the set of master equations [77] dP 0 (t)…”

“…The dynamics of approaching the stationary state can be understood from analyzing a local relaxation function, defined as R n (t) ≡ Pn(t)−P (s) n Pn(0)−P (s) n [34]. Simple calculations yield the following expressions for the local accumulation times [77],…”