Fine intercellular connections in development: TNTs, cytonemes, or intercellular bridges?

Abstract

Intercellular communication is a fundamental property of multicellular organisms, necessary for their adequate responses to changing environment. Tunneling nanotubes (TNTs) represent a novel means of intercellular communication being a long cell-to-cell conduit. TNTs are actively formed under a broad range of stresses and are also proposed to exist under physiological conditions. Development is a physiological condition of particular interest, as it requires fine coordination. Here we discuss whether protrusions shown to exist during embryonic development of different species could be TNTs or if they represent other types of cell structure, like cytonemes or intercellular bridges, that are suggested to play an important role in development.

Keywords: TNTs; cytonemes; intercellular bridges; intercellular communication; tunneling nanotubes.

Figure 1. FIGURE 1: “Thick” and “thin” TNT connections.

Cryo-electron microscopy shows that TNTs can either be a single thick connection or a bundle of thin individual TNTs (iTNTs). Both open-ended and closed-ended protrusions can be present within a bundle. Each iTNT contain actin bundles, can contain vesicles and mitochondria. Thin and short membrane threads connect several iTNTs, which appear to grow in opposite directions. Adapted from Sartori-Rupp et al. [31].

Figure 2. FIGURE 2: Similarities and differences between TNTs, cytonemes and intercellular bridges at optical microscopy level.

TNTs (A) and cytonemes (B) have similar morphologies, they contain actin but not tubulin. However, TNTs are open-ended and allow cytoplasm continuity, while cytonemes are closed-ended, and allow protein-protein interactions. Intercellular bridges (C) are open-ended, but are generally shorter and wider than TNTs. Some intercellular bridges were also reported to contain tubulin. All three types of cell structures are able to transfer cargo. However, while cytonemes transfer vesicles on their surface, TNTs and intercellular bridges are able to transfer such organelles as mitochondria in their lumen. As TNT diameter is generally smaller than the diameter of mitochondria, the transfer requires membrane bulging.

Figure 3. FIGURE 3: Mechanisms of formation of TNTs, cytonemes and intercellular bridges, according to optical live microscopy.

TNTs can be formed by cell dislodgment (A), when cells first make contact and then form a nanotube while migrating in the opposite directions. Morphologically it resembles the formation of intercellular bridges (B). However, intercellular bridges are formed only between dividing cells by incomplete cytokinesis, while TNTs can be formed by cells of different origin. Thus, formation of TNTs requires membrane fusion prior to cell dislodgement, while formation of intercellular bridges requires inhibition of abscission after cell division. Another mechanism of TNT formation, called “actin-driven”, takes place when either one (C) or both (E) of the cells induce the outgrowth of filopodia-like protrusions. Similar mechanism is shown for cytonemes. Cytonemes can be formed from producing to receiving cells and vice versa (D), as well as from both of them (F). However, in case of cytonemes, the outgrowth is finalized by establishing the contact, while TNT formation require subsequent membrane fusion.