Moving away from the midline: new developments for Slit and Robo

Abstract

SummaryIn most tissues, the precise control of cell migration and cellcell interaction is of paramount importance to the development of a functional structure. Several families of secreted molecules have been implicated in regulating these aspects of development, including the Slits and their Robo receptors. These proteins have well described roles in axon guidance but by influencing cell polarity and adhesion, they participate in many developmental processes in diverse cell types. We review recent progress in understanding both the molecular mechanisms that modulate Slit/Robo expression and their functions in neural and non-neural tissue. Key words: Axon guidance, Cell migration, Cell-cell interaction IntroductionIn most organisms, the central nervous system (CNS) develops along a bilateral axis of symmetry located at the midline (Placzek and Briscoe, 2005). During development, the ventral midline or floor plate acts as an organiser through the secretion of diffusible proteins (Placzek and Briscoe, 2005;Gore et al., 2008), which control the growth of axons and dendrites and the migration of neurons across the midline. In the forebrain, glial or neuronal cells delineate the midline (see Glossary, Box 1) and also control axon guidance. For more than two decades, many developmental neurobiologists have tried to understand the mechanisms that control midline crossing in the CNS and to answer some key questions. Firstly, how are commissural axons (see Glossary, Box 1) attracted to the midline and how do their growth cones (see Glossary, Box1) receive and integrate the multiple and contrasting signals released by midline cells? Secondly, what are the molecular and signalling changes that enable commissural axons to leave the midline and often to switch to a longitudinal growth mode? All midline-derived axon guidance factors are expressed at other locations in many developing and mature tissues, where they control a wide range of biological processes.Roundabout receptors (Robo) and their Slit ligands form one of the most crucial ligand-receptor pairings among the axon guidance molecules. Robos were identified in Drosophila in a mutant screen for genes that control the midline crossing of commissural axons (Kidd et al., 1998;Seeger et al., 1993). Similarly, Slit was discovered in Drosophila as a protein secreted by midline glia (Rothberg et al., 1988;Rothberg et al., 1990). Homologues of both proteins have since been discovered in many species (for a review, see . However, the Slit/Robo couple not only functions in axon guidance but also in a variety of developmental Development 137, 1939Development 137, -1952Development 137, (2010 Commissural axons Axons with cell bodies (somata) located on one side of the central nervous system (CNS) that project axons across the midline to contact target cells on the opposite side. Growth cone A specialised bulbous enlargement at the end of growing axons that is characterised by dynamic filamentous extensions, known as filopodia. They sense the environment and respond to adhesi...

Tuning Collective Cell Migration by Cell–Cell Junction Regulation

“…Robo receptors belong to the superfamily of IgCAMs and engage in both homophilic and heterophilic interactions (Hivert et al 2002). Slits are the principal ligands for the Robo receptors (Kidd et al 1999), which, together with heparan sulphates, form a ternary complex required for signaling (Ypsilanti et al 2010). The cytoplasmic domains of Robo do not possess catalytic activities and, therefore, interact with different signaling molecules to exert their specific effects; these include netrin and several GTPase activating proteins (GAPs) and GEFs that control actin cytoskeletal dynamics by regulating the activity of RhoA, Rac1, and Cdc42 (Ypsilanti et al 2010).…”

“…Slits are the principal ligands for the Robo receptors (Kidd et al 1999), which, together with heparan sulphates, form a ternary complex required for signaling (Ypsilanti et al 2010). The cytoplasmic domains of Robo do not possess catalytic activities and, therefore, interact with different signaling molecules to exert their specific effects; these include netrin and several GTPase activating proteins (GAPs) and GEFs that control actin cytoskeletal dynamics by regulating the activity of RhoA, Rac1, and Cdc42 (Ypsilanti et al 2010). The activity of Slit/Robo, including adhesion, is controlled by transcriptional regulation and endocytosis and degradation (Keleman et al 2005).…”

Intraislet SLIT–ROBO signaling is required for beta-cell survival and potentiates insulin secretion

“…Mammalian homologs of Slit and Robo with functions outside of axon guidance have since been identified (18,19). Slit ligands have been implicated in liver, kidney, lung, and mammary development by modulating cell adhesion, migration, differentiation, and death (18,20,21).…”

A-kinase Anchoring Protein 79/150 Recruits Protein Kinase C to Phosphorylate Roundabout Receptors

“…There are four members of the Robo family of chemotactic guidance receptors (40). Therefore, it seemed logical to explore the possibility that AKAP79/150 may associate with other Robo receptor isoforms.…”

“…Therefore, it seemed logical to explore the possibility that AKAP79/150 may associate with other Robo receptor isoforms. However, only Robo1, -2, and -3 are expressed in neurons (40). Therefore, AKAP79 pull-down experiments were conducted with GST fusion proteins encompassing the cytoplasmic tails of Robo1, Robo2, and Robo3.…”