Cytonemes as specialized signaling filopodia

Abstract

Development creates a vast array of forms and patterns with elegant economy, using a small vocabulary of pattern-generating proteins such as BMPs, FGFs and Hh in similar ways in many different contexts. Despite much theoretical and experimental work, the signaling mechanisms that disperse these morphogen signaling proteins remain controversial. Here, we review the conceptual background and evidence that establishes a fundamental and essential role for cytonemes as specialized filopodia that transport signaling proteins between signaling cells. This evidence suggests that cytoneme-mediated signaling is a dispersal mechanism that delivers signaling proteins directly at sites of cell-cell contact.

Keywords: Cytoneme plasticity; Cytoneme transfer; Drosophila; Filopodia; Gradient; Morphogen.

Fig. 1.

Transfer of Drosophila signaling proteins at sites of direct cell-cell contact. Four contexts are illustrated in which signaling proteins transfer between producing and receiving cells at synapses. (A) In the developing visual system, the N-terminal fragment of processed Hedgehog (Hh, red bar) separates from the C-terminal fragment (orange bar) and is released to a post-synaptic neuron in the lamina after transport down a retinal axon (Chu et al., 2006; Huang and Kunes, 1996). (B) The Drosophila EGF-like protein Spitz (Spi, blue) moves by a similar mechanism in retinal neurons (Yogev et al., 2010). (C) Drosophila Wingless (Wg, red) is released in a vesicular form at developing neuromuscular synapses (Korkut et al., 2009). (D) Decapentaplegic (Dpp, red circles) moves from wing disc cells to air sac primordium (ASP) cells at synapses that form at cytoneme tips (Roy et al., 2014). Hh (green circles) moves from P compartment cells to cells across the compartment border along cytonemes (Callejo et al., 2011).

Fig. 2.

Cytonemes of the eye and wing imaginal discs. (A) An eye disc in which the morphogenetic furrow has progressed anteriorly across part of the eye field, highlighting two types of cytoneme (black lines) extending from cells anterior to the furrow: (1) cytonemes oriented toward the equator; and (2) cytonemes oriented toward the furrow and populated with EGFR-containing puncta (green dots). (B) A wing disc with the concentration gradient of Dpp depicted (red) showing cells in the wing blade primordium that extend cytonemes toward the Dpp-expressing cells and that are populated with Tkv-containing puncta (blue dots). (C) A wing disc and its associated trachea with ASP cells depicted with: (1) cytonemes that extend from the ASP tip to FGF-expressing disc cells (purple) and that are populated with FGFR-containing puncta (black dots); and (2) cytonemes that extend from the medial region to Dpp-expressing disc cells and are populated with Tkv-containing puncta (blue dots).