Cytoneme-mediated morphogenesis

Morphogen protein gradients play an essential role in the spatial regulation of patterning during embryonic development. The most commonly accepted mechanism of protein gradient formation involves the diffusion and degradation of morphogens from a localized source. Recently, an alternative mechanism has been proposed, which is based on cell-to-cell transport via thin, actin-rich cellular extensions known as cytonemes. It has been hypothesized that cytonemes find their targets via a random search process based on alternating periods of retraction and growth, perhaps mediated by some chemoattractant. This is an actin-based analog of the search-and-capture model of microtubules of the mitotic spindle searching for cytochrome binding sites (kinetochores) prior to separation of cytochrome pairs. In this talk, we introduce a search-and-capture model of cytoneme-based morphogenesis, in which nucleating cytonemes from a source cell dynamically grow and shrink until making contact with a target cell and delivering a burst of morphogen. We model the latter as a one-dimensional search process with stochastic resetting, finite returns times and refractory periods. We use a renewal method to calculate the splitting probabilities and conditional mean first passage times (MFPTs) for the cytoneme to be captured by a given target cell. We show how multiple rounds of search-and-capture, morphogen delivery, cytoneme retraction and nucleation events lead to the formation of a morphogen gradient. We proceed by formulating the morphogen bursting model as a queuing process, analogous to the study of translational bursting in gene networks. We end by briefly discussing current work on a model of cytoneme-mediated within-host viral spread.