Regulatory mechanisms of cytoneme-based morphogen transport

Abstract

During development and tissue homeostasis, cells must communicate with their neighbors to ensure coordinated responses to instructional cues. Cues such as morphogens and growth factors signal at both short and long ranges in temporal- and tissue-specific manners to guide cell fate determination, provide positional information, and to activate growth and survival responses. The precise mechanisms by which such signals traverse the extracellular environment to ensure reliable delivery to their intended cellular targets are not yet clear. One model for how this occurs suggests that specialized filopodia called cytonemes extend between signal-producing and -receiving cells to function as membrane-bound highways along which information flows. A growing body of evidence supports a crucial role for cytonemes in cell-to-cell communication. Despite this, the molecular mechanisms by which cytonemes are initiated, how they grow, and how they deliver specific signals are only starting to be revealed. Herein, we discuss recent advances toward improved understanding of cytoneme biology. We discuss similarities and differences between cytonemes and other types of cellular extensions, summarize what is known about how they originate, and discuss molecular mechanisms by which their activity may be controlled in development and tissue homeostasis. We conclude by highlighting important open questions regarding cytoneme biology, and comment on how a clear understanding of their function may provide opportunities for treating or preventing disease.

A macrophage subpopulation promotes airineme-mediated intercellular communication in a Matrix Metalloproteinase-9 dependent manner

“…Several features of airinemes distinguish them from other signaling cellular protrusions, such as cytonemes and tunneling nanotubes. One of the most striking differences is that airinemes require macrophages as ‘delivery vehicles’ for relaying airineme vesicles to the target melanophores intermingled with non-target cells (Daly et al, 2022; Eom, 2020). Airinemes may need these cells to help them extend through the densely packed tissue environment, especially airinemes with large vesicles at their tips (Hirata et al, 2003).…”

“…These can be classified based on their cytoskeletal composition, mode of signal delivery, morphology, and more. The growing list of such protrusions that have been identified include cytonemes, tunneling nanotubes, airinemes, intercellular bridges, and migrasomes (Caviglia and Ober, 2018; Daly et al, 2022; Gonzalez-Mendez et al, 2019; Jiang et al, 2019). They are found in a variety of cell types and species, such as fruit fly, sea urchin, zebrafish, and cultured mammalian cells, and their signaling roles have been functionally validated (Eom, 2020).…”

Cytoneme-mediated intercellular signaling in keratinocytes essential for epidermal remodeling

“…Our observation revealed severe disorganization of microridges in the il17rd overexpressed keratinocytes, coupled with a significant down-regulation of Cdc42 GTPase expression in these cells (Figure 6C, D). These data suggest that IL-17 signaling negatively regulates cytoneme extension by down-regulating Cdc42 that are essential in control of actin cytoskeleton (Daly et al, 2022;Hall, 1998;Jaffe and Hall, 2005;Stanganello et al, 2015). We then crossed two transgenic lines: Tg(krt4:TetGBDTRE-v2a-cdc42DN) and either Tg(krt4:nVenus-v2a-il17rd) or Tg(krt4:il17ra1a-v2a-mCherry).…”

Extracellular Vesicles and Membrane Protrusions in Developmental Signaling

“…To facilitate our discussion of EVs in development, we briefly discuss three categories of filamentous structures: membrane passages, fine cellular protrusions, and adherent cellular protrusions ( Table 2 ). Many recent, extensive reviews elaborate on the characteristics and mechanisms behind these protrusions [ 34 , 65 , 66 , 67 ]. For the purpose of this review, protrusions and filopodia will be used interchangeably when specific types of protrusions (i.e., membrane passages) are not defined.…”