Neogenin interacts with RGMa and Netrin-1 to guide axons within the embryonic vertebrate forebrain

Abstract

In the embryonic forebrain, pioneer axons establish a simple topography of dorsoventral and longitudinal tracts. The cues used by these axons during the initial formation of the axon scaffold remain largely unknown. We have investigated the axon guidance role of Neogenin, a member of the immunoglobulin (Ig) superfamily that binds to the chemoattractive ligand Netrin-1, as well as to the chemorepulsive ligand repulsive guidance molecule (RGMa). Here, we show strong expression of Neogenin and both of its putative ligands in the developing Xenopus forebrain. Neogenin loss-of-function mutants revealed that this receptor was essential for axon guidance in an early forming dorsoventral brain pathway. Similar mutant phenotypes were also observed following loss of either RGMa or Netrin-1. Simultaneous partial knock downs of these molecules revealed dosage-sensitive interactions and confirmed that these receptors and ligands were acting in the same pathway. The results provide the first evidence that Neogenin acts as an axon guidance molecule in vivo and support a model whereby Neogenin-expressing axons respond to a combination of attractive and repulsive cues as they navigate their ventral trajectory.

The Crystal Structure of Netrin-1 in Complex with DCC Reveals the Bifunctionality of Netrin-1 As a Guidance Cue

“…Netrin-1 binding to DCC induces chemo-attraction (Keino-Masu et al, 1996), but this response is turned into repulsion if another receptor, uncoordinated-5 (UNC5) co-exists with DCC (Colamarino and Tessier-Lavigne, 1995). Other known netrin-1 receptors that assist in axon guidance are DSCAM (Ly et al, 2008; Andrews et al, 2008; Liu et al, 2009) and Neogenin (Wilson and Key, 2006). More receptors are expected to be involved including membrane-bound proteoglycans (Rajasekharan and Kennedy, 2009).…”

Up-regulation of neogenin-1 increases cell proliferation and motility in gastric cancer

“…Neogenin-1 is present in tissues where active growth takes place, and overexpression of neogenin-1 has been observed in a wide variety of human cancers including those of the breast, pancreas, cervix, colon, medulloblastoma and rectum [17-19]. Previous studies have also shown that neogenin-1 may promote cell migration and cell-cell adhesion in human vascular smooth muscle in addition to zebrafish neurectoderm [9, 20]. Also, neogenin-1 is involved in various aspects of cancer progression and metastasis [9].…”

Neogenin-mediated Hemojuvelin Shedding Occurs after Hemojuvelin Traffics to the Plasma Membrane

“…Neogenin is a membrane protein and widely expressed in most tissues, including liver and skeletal muscle (30 -34). The interactions of neogenin with RGMa and netrins are essential for neural development (35,36). Our previous study showed that the interaction with neogenin is required for HJV release from muscle cells (20).…”