The Robo3 receptor, a key player in the development, evolution, and function of commissural systems

Abstract

Roundabout receptors are known to mediate Slit-dependent repulsive signaling. However in vertebrates, mounting evidence suggest that Robo3 is an unconventional Robo receptor regarding both its expression and function. From its initial description, the Robo3 receptor has been tightly associated with the development of specific axons, called commissural, that connect both sides of the nervous system. Many studies using transgenic mouse models showed that Robo3 expression is mandatory for commissural axon guidance to the floor plate. Moreover, mutations in human ROBO3 are responsible for a rare neurological disease in which patients also display midline crossing defects. Robo3 was initially thought to counteract Slit/Robo repulsion. However, recent studies support an alternative model where Robo3 potentiates midline attraction. These studies support a complex, central and multifaceted role of Robo3 in controlling the development of commissural circuits. Furthermore, the analysis of Robo3 evolution in vertebrates points out the specificity of this receptor in the mammalian lineage, suggesting mechanistic and functional divergence of Robo3 in mammals compared to a more traditional function in other vertebrates. Here, we review the current knowledge about Robo3 function, from the regulation of its expression to signaling. We also present evidence for a high variability of Robo3 splice variants in vertebrates. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 876-890, 2017.

Keratan sulfate (KS)‐proteoglycans and neuronal regulation in health and disease: the importance ofKS‐glycodynamics and interactive capability with neuroregulatory ligands

“…). The Robo 3 receptor is intimately associated with the development and function of the commissural axons potentiating mid‐line attractive forces through interaction with Slit proteins which guide the commissural neurons across the developing spinal cord (Friocourt and Chedotal ), a process which is also aided by the semaphorins and in particular semaphorin 3B (Pignata et al . ) and 6B (Andermatt et al .…”

The Spectrum of <i>ROBO</i>3 Mutations in Horizontal Gaze Palsy with Progressive Scoliosis: An Update

“…The mutations are highly diverse, and indistinguishable phenotypes result from ROBO3 nonsense, frame-shift, splice-site, or missense mutations, supporting a complete loss of ROBO3 function [26]. Some mutations are predicted to induce a premature stop-codon, associated with expression of a truncated protein or mRNA degradation vianonsense mediated decay (NMD) [27]. In addition, we report in Table 1 a lot of variants of uncertain pathological significance, described for the first time by Illumina Clinical Services (Laboratory Illumina, 2016).…”

Construction and reconstruction of brain circuits: normal and pathological axon guidance

“…This receptor is expressed transiently by commissural axons in mouse spinal cord, midbrain and hindbrain and then is rapidly down‐regulated after the axons have crossed the FP (Belle et al ; Zelina et al ). It is expressed in human pontine neurons (Jen et al ) and in hindbrain and spinal cord commissural axons of birds (Philipp et al ; Escalante et al ; Friocourt and Chédotal ) and other vertebrate species (Friocourt et al ). The absence of Robo3 leads to a complete loss of several commissures in mice and in humans (Jen et al ; Marillat et al ; Sabatier et al ; Renier et al ; Michalski et al ).…”