Mechanisms and functions of extracellular vesicle release in vivo-What we can learn from flies and worms

Abstract

Cells from bacteria to man release extracellular vesicles (EVs) that contain signaling molecules like proteins, lipids, and nucleic acids. The content, formation, and signaling roles of these conserved vesicles are diverse, but the physiological relevance of EV signaling in vivo is still debated. Studies in classical genetic model organisms like C. elegans and Drosophila have begun to reveal the developmental and behavioral roles for EVs. In this review, we discuss the emerging evidence for the in vivo signaling roles of EVs. Significant effort has also been made to understand the mechanisms behind the formation and release of EVs, specifically of exosomes derived from exocytosis of multivesicular bodies and of microvesicles derived from plasma membrane budding called ectocytosis. In this review, we detail the impact of flies and worms on understanding the proteins and lipids involved in EV biogenesis and highlight the open questions in the field.

Keywords: C. elegans; Drosophila; behavior; development; ectosome; exosome; extracellular vesicle; genetics; microvesicle; signaling.

Figure 1.

Mechanisms of extracellular vesicle release. (A) Extracellular vesicles can be released by direct budding of the plasma membrane to form microvesicles. Extracellular vesicles can also be released by the fusion of multivesicular bodies (MVBs) with the plasma membrane to release exosomes. To form MVBs, endosomes must first bud vesicles into their lumen, called intraluminal vesicles (ILVs). (B) Plasma membrane budding away from the cytoplasm requires Rab GTPases and the ESCRT complex. Lipids also play an important role in microvesicle budding, with phosphatidylinositols recruiting membrane-sculpting proteins and cone-shaped phosphatidylethanolamine inducing membrane curvature. (C) The budding of ILVs into MVBs also requires Rab and Ral GTPases and the ESCRT complex. (D) The fusion of MVBs with the plasma membrane to release exosomes requires vesicle tethering and fusion factors, such as Rab and Ral GTPases, SNAREs, and the V-type ATPase.

Figure 2.

In vivo functions of extracellular vesicles in genetic model organisms. (A) In C. elegans embryos, excessive microvesicle release disrupts gastrulation movements. (B) In C. elegans larvae and adults, seam cells (brown rectangle) release exosomes to build the alae, longitudinal ridges on the cuticle. (C) In C. elegans adult males, ciliated neurons release EVs important for male mating behavior. (D) In Drosophila larvae, the wing imaginal disc is patterned by morphogens carried on EVs that induce the wing axes. (E) The neuromuscular junction also releases morphogens on EVs that are important for synaptic development. (F) Drosophila adult males release exosomes important for female mating behavior.