Specialized filopodia: at the 'tip' of morphogen transport and vertebrate tissue patterning

Abstract

For over a century, biologists have strived to unravel the mechanisms that establish how cells are informed of their position in the embryo and differentiate to give rise to complex organs and structures. However, the historical idea that one predominant mode of ligand transport, largely accounted for by free diffusion, can explain how all signaling molecules, known as morphogens, control tissue patterning has greatly hindered our ability to fully appreciate the complexities driving the delivery and reception of signaling molecules at a distance. In reality, a cell's shape, morphology, and location change continuously as development progresses. Thus, cellular context poses distinct challenges for morphogen transport in each unique cellular environment. Emerging studies reveal that some cells overcome such obstacles in an unexpected manner: via long, cellular projections, or specialized filopodia, that link distant cells and traffic signaling components. Here, we will review recent findings describing specialized filopodia and discuss the potential mechanisms and implications for filopodia-based long-range cell signaling and communication, particularly within the developing vertebrate embryo.

Figure 1. Specialized filopodia allow cells to overcome barriers to morphogen transport that arise from complex cellular landscapes

(A) In early embryos, cells often become separated by the expansive, fluid-filled blastocoel; however, communication between distant cells is commonly required for proper development. Simple diffusion would result in the unrestricted travel of morphogens (red circles) in many directions, rather than directly towards the intended responding cell (blue; left panel). Specialized filopodia linking distant cells would provide a platform for the direct, long-range transport and delivery of signaling molecules (right panel). (B) In early zebrafish embryos, signals originating from distant organizers, such as Wnt8a present at the blastoderm margin (red line), influence distant cells in order to specify distinct anatomical structures. For example, Wnt8a patterns the future midbrain-hindbrain boundary (MHB), which forms between Otx2 and Gbx1/2 expression domains (left panel). Simple diffusion of a ligand (red circles) cannot explain the directed, lateral distribution of signaling molecules towards distant responding cells in the MHB. However, these epithelial cells extend specialized filopodia, to which Wnt8a ligand is localized (right panel), suggesting that Wnt8a can be directly delivered to responding cells multiple cell diameters away. (C) The developing vertebrate limb consists of a dense network of mesenchymal cells, each containing specialized filopodia extending in many directions (left panel) and individual cells must integrate many different signals (left panel insert), including gradients of Shh, FGF, and Wnt. Shh ligand (red circles, right panel) travels, in the form of distinct particles, along the extracellular surface of filopodia extending from Shh producing cells (red cell), while Shh co-receptors Cdo and Boc (blue rectangles) localize to filopodia of adjacent responding cells (blue cells; right panel and insert). These results suggest that contact-mediated release propagated by specialized filopodia contributes to the delivery of ligands at a distance.