Signaling at a distance mediated by vesicles on novel cellular protrusions

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Abstract The importance of elucidating the molecular mechanisms that underlie cell-to-cell communication is impossible to overstate. Intercellular communication formed the foundation for the evolution of metazoans; then as organisms grew larger, the transduction of signals over distance assumed crucial importance. Long-range signaling in which cells must communicate accurately over several cell diameters is vital both during development and for homeostasis. Deficiencies in the proper execution of the process often results in disease or death. The study of human cancers provides numerous examples of what can happen when a component of a signaling process goes bad. Numerous signaling pathways have been characterized over the past few decades, and a large number of the molecules involved in intercellular signal transduction, both extracellular ligands and their cognate cellular receptors, have been identified. However, gaps still exist at present in what is known of the means by which signals are propagated. The diffusion-based propagation model suggested more than 60 years ago has been the dominant paradigm. This has been particularly true in developmental biology regarding the impact of concentration gradients that are predicted to form as signaling molecules passively diffuse through tissues. Nevertheless, debate has continued on how well such models can explain the precision by which various signals are transmitted over distances of multiple cell diameters. Recently, several research groups including our own have shown that signaling molecules can also be delivered accurately over such distances by direct cell-cell contact that involves the extension of long, thin cellular protrusions (also referred to as signaling filopodia). We have identified a novel variety of such protrusions extending from zebrafish pigment cells that we have named ‘airinemes.’ Airinemes have been seen to be an indispensable component of stripe pattern formation in zebrafish epidermis based on their mediation of long-distance Delta-Notch signaling between pigment cell types. Intriguingly, we have also discovered that this airineme-mediated long-range intercellular signaling is dependent on participation of skin-resident macrophages. Collectively, our findings denote that mechanisms of signal propagation can involve much more than mere passive diffusion of molecules. Moreover, we subsequently found airinemes protruding from other cell types of the epidermis, e.g., keratinocytes, suggesting that airineme-mediated signaling may be a general mechanism in at least that tissue if not others. Although the airineme/macrophage-mediated signaling that we have described has been clearly validated as occurring in vivo, the molecular and cellular details of how this signaling is accomplished are still not sufficiently described. Those details are a crucial first step in linking anomalies in this mode of signaling with the occurrence of various pathologies in vertebrates. In this proposal we will address questions essential to establishing how airinemes achieve target specificity, whether there is a particular subset of skin-resident macrophages that promotes airineme-mediated signaling, and determining what functions airinemes provide in zebrafish keratinocytes. The answers to these questions will not only expand our view of fundamental cellular strategies employed in paracrine signaling but could also provide a basis for detecting where biomedicine might be able to intervene in the process when signaling goes awry in human pathophysiology.