Impulsive signaling model of cytoneme-based morphogen gradient formation

Abstract

Morphogen protein gradients play a vital role in regulating spatial pattern formation during development. The most commonly accepted mechanism of protein gradient formation involves the diffusion and degradation of morphogens from a localized source. However, there is growing experimental evidence for a direct cell-to-cell signaling mechanism via thin actin-rich cellular extensions known as cytonemes. Recent modeling studies of cytoneme-based morphogenesis in invertebrates ignore the discrete nature of vesicular transport along cytonemes, focusing on deterministic continuum models. In this paper, we develop an impulsive signaling model of morphogen gradient formation in invertebrates, which takes into account the discrete and stochastic nature of vesicular transport along cytonemes. We begin by solving a first passage time problem with sticky boundaries to determine the expected time to deliver a vesicle to a target cell, assuming that there is a ‘nucleation’ time for injecting the vesicle into the cytoneme. We then use queuing theory to analyze the impulsive model of morphogen gradient formation in the case of multiple cytonemes and multiple targets. In particular, we determine the steady-state mean and variance of the morphogen distribution across a one-dimensional array of target cells. The mean distribution recovers the spatially decaying morphogen gradient of previous deterministic models. However, the burst-like nature of morphogen transport can lead to Fano factors greater than unity across the array of cells, resulting in significant fluctuations at more distant target sites.