Emerging roles for neogenin and its ligands in CNS development

Abstract

It is now well established that the netrin guidance cues and their receptors comprise a major molecular guidance system driving axon pathfinding during nervous system development. One netrin receptor, neogenin, is now emerging as a key regulator of many developmental processes throughout the embryo. Unexpectedly, a new family of neogenin ligands, the repulsive guidance molecule (RGM) family, has recently been identified. The functional outcome of neogenin activation is dictated by both the nature of the ligand as well as the developmental context. Netrin-1-neogenin interactions mediate chemoattractive axon guidance, while RGMa-neogenin interactions repel axons. Neogenin is required for the establishment of the pseudostratified epithelium of the neural tube, probably by promoting cell adhesion. In addition, a role for RGMa and neogenin in neuronal differentiation has been demonstrated. While neogenin signaling cascades are poorly understood, the opposing responses of neogenin to RGMa and netrin-1 in the context of axon guidance indicates that neogenin signaling is complex and subject to tight spatiotemporal regulation. In summary, neogenin is a multifunctional receptor regulating diverse developmental processes. Thus, its contribution to neural development is proving to be considerably more extensive than originally predicted.

Neogenin and RGMa Control Neural Tube Closure and Neuroepithelial Morphology by Regulating Cell Polarity

“…In contrast, our data suggest that the outcome of RGMa-Neogenin interactions in the context of neurulation is the establishment or maintenance of cell polarity and epithelial integrity. A similar situation occurs during mouse mammary gland development, where Netrin-1-Neogenin interactions are required to stabilize the structure of the developing mammary epithelium (Srinivasan et al, 2003;De Vries and Cooper, 2008). That RGMa is important for neural tube closure is further supported by the occurrence of exencephaly in RGMa loss-of-function mouse embryos (Niederkofler et al, 2004).…”

“…To date, the molecular mechanisms promoting NF elevation have not been identified. Here we demonstrate that NF elevation is dependent on the axon guidance receptor, Neogenin (Vielmetter et al, 1994;Keeling et al, 1997;De Vries and Cooper, 2008).…”

RGMA and IL21R show association with experimental inflammation and multiple sclerosis

“…35 The RGMA protein and its receptor, neogenin, have thus mainly been implicated in nervous system development. [36][37][38][39] The role of RGMA in the nervous system and the fact that Eae30 showed linkage exclusively to EAE and not PIA, made it a particularly interesting candidate for studies of association with MS; however, as discussed below variants of the gene may well differentially regulate immune mechanisms. In addition, RGMA is not only expressed in neural cells, but also in macrophages and/or microglia and infiltrating leukocytes, as demonstrated in a spinal cord injury model.…”

La chimie-click débusque les substrats d’ADAM10

“…Un autre groupe de cibles potentielles d'ADAM10 joue un rôle dans le ciblage axonal. Il s'agit notamment de la néoge-nine (NEO1), récepteur de molécules de guidage axonal dont la nétrine [10], et de plusieurs membres de la famille des molécules d'adhérence L1 [11]. Les auteurs démontrent par ailleurs, pour renforcer l'hypothèse d'un rôle d'ADAM10 dans le ciblage axonal, des défauts de ce ciblage dans le bulbe olfactif et l'hippocampe chez les animaux knock-out pour ADAM10.…”