Some of the processing events take place in endocompartments. The trafficking and endosomal compartmentalization of required processing components for many potent ligands (such as EGF ligands, TGFβ-ligands, Wnt, Notch, and others) fine-tunes when and where active ligand reaches the surface. Endosomal regulation of ligand processing and trafficking is

certain to impact many neurodevelopmental processes (for review, see Shilo and Schejter, 2011). Shilo and coworkers discovered a striking mechanism by which the generation of active ligand is tightly controlled by subcompartmentalization of a processing component (Yogev et al., 2008). The EGF ligand Spitz (Spi) controls multiple developmental pathways in Drosophila, including fate decisions in the developing eye. Spi is synthesized in a proform in the Selleck SCH727965 ER and requires proteolytic processing by the protease rhomboid for activity. A complex, regulated interplay between Spi, its ER chaperone Star, and rhomboid allows for precise

regulation of generation and secretion of active Spi. Star ensures traffic of pro-Spi to a rab4/rab14-positive endosomal compartment, where it encounters rhomboid, is cleaved, and Proteasome inhibitor is then secreted as an active ligand. Subsequent cleavage of Star by rhomboid presumably bestows directionality to Spi transport. Wnt signaling is also regulated by multiple factors and trafficking is emerging as an important node for both ligand transport to the surface (Coudreuse and Korswagen, 2007) and signaling. Wnt signaling is dependent on retromer (Coudreuse et al., 2006 and Prasad and Clark, 2006), a complex of proteins needed for retrograde transport from endosomes to the TGN. Why would Wnt signaling depend on retromer function? It was shown in multiple beautiful studies that Wnt requires the membrane receptor Wingless (Wls) for Golgi exit. Retromer function is then required to return Wls from the cell surface via endosomes to the Golgi where it can mediate another round of Wnt trafficking (Belenkaya et al., 2008, Franch-Marro et al., 2008, Pan et al., 2008, Port et al., 2008 and Yang et al., 2008). These examples

highlight the intimate interplay between biosynthetic and endosomal trafficking. Neural development and neuronal function in the adult Terminal deoxynucleotidyl transferase nervous system are regulated by large numbers of membrane receptors that signal upon ligand binding. The biology of the receptors, the ligands, and the signaling cascades is complex and only incompletely understood. In this review, we focused on the roles of endocytosis and subsequent endosomal trafficking in regulating this biology. The first and most studied role of endocytosis is to regulate the distribution in time and space of various receptors on the cell surface. The surface distribution contributes to setting responsiveness to extracellular cues and therefore influences the strength of signaling.