Signaling by Cellular Protrusions

Cytonemes (thin red) extended from a cell in fruit fly [Wikipedia Commons].

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 from a localized source. Recently, there is growing experimental evidence for an alternative mechanism, which is based on direct cell contact via thin actin-rich cellular extensions known as cytonemes. We have developed several mathematical models of cytoneme-based morphogenesis at different levels of detail.

Arinemes relayed by macrophages

Airineme (green thin) is relayed by macrophages (blue) [Dae Seok Eom and David Parichy].

Another example of protrusion-based pattern formation has been observed in zebrafish. Similar to cytonemes in vertebrates, airinemes are dynamic cell extensions. One unique feature of airinemes is that their tips are relayed by macrophages. As yet, no one knows how this mechanism is evolutional benefit quantitatively. In an ongoing collaboration with Jun Allard, Dae-Seok Eom and Sohyeon Park, we are investigating this mechanism based on a stochastic model.

  • S. Park, H. Kim, D.S. Eom, and J. Allard, “Zebrafish airinemes and optimally curvature for search,” In preparation, 2019+.

Signaling “bursts” via cytonemes

Search-and-capture model of dynamic cytoneme along a one dimensional array of cells. 

In vertebrates, cytonemes have a dynamic mechanism for transporting morphogens to targets. Morphogens are localized at the cytoneme tip, and are released immediately once the tip makes a contact with a target. This process generates morphogen “bursting” in a target cell. A crucial issue for this form of transport is how cytoneme tips find their targets. Two pathfinding hypotheses have been proposed: (i) random searching by rapid extension and retraction, or (ii) attraction by a chemoattractant. Here we analyze a doubly stochastic process for cytoneme-based search-and-capture in vertebrates. To deal with the complex nature of the stochastic process, we made use of some results in probability theory: the strong Markov property and queuing theory.

Cytoneme transport mechanisms for gradient formation

Effect of cytoneme transport mechanisms on morphogen gradient formation in invertebrates.

In invertebrates, there are several hypotheses regarding the nature of interactions between cytonemes and target cells. Cytonemes from a single source can link to multiple target cells such that the number of cytonemes per target is non-uniform. Moreover, contact between a cytoneme tip and a target cell could involve a direct contact or an indirect contact mediated by a synapse. Here we compare the several different hypotheses concerning the contact mechanism between cytoneme tips and target cells in invertebrates based on PDE models.