Spatiotemporal Expression of Repulsive Guidance Molecules (RGMs) and Their Receptor Neogenin in the Mouse Brain

Abstract

Neogenin has been implicated in a variety of developmental processes such as neurogenesis, neuronal differentiation, apoptosis, migration and axon guidance. Binding of repulsive guidance molecules (RGMs) to Neogenin inhibits axon outgrowth of different neuronal populations. This effect requires Neogenin to interact with co-receptors of the uncoordinated locomotion-5 (Unc5) family to activate downstream Rho signaling. Although previous studies have reported RGM, Neogenin, and/or Unc5 expression, a systematic comparison of RGM and Neogenin expression in the developing nervous system is lacking, especially at later developmental stages. Furthermore, information on RGM and Neogenin expression at the protein level is limited. To fill this void and to gain further insight into the role of RGM-Neogenin signaling during mouse neural development, we studied the expression of RGMa, RGMb, Neogenin and Unc5A-D using in situ hybridization, immunohistochemistry and RGMa section binding. Expression patterns in the primary olfactory system, cortex, hippocampus, habenula, and cerebellum were studied in more detail. Characteristic cell layer-specific expression patterns were detected for RGMa, RGMb, Neogenin and Unc5A-D. Furthermore, strong expression of RGMa, RGMb and Neogenin protein was found on several major axon tracts such as the primary olfactory projections, anterior commissure and fasciculus retroflexus. These data not only hint at a role for RGM-Neogenin signaling during the development of different neuronal systems, but also suggest that Neogenin partners with different Unc5 family members in different systems. Overall, the results presented here will serve as a framework for further dissection of the role of RGM-Neogenin signaling during neural development.

Repulsive guidance molecules (RGMs) and neogenin in bone morphogenetic protein (BMP) signaling

“…Unlike DCC, whose expression in vertebrates is primarily restricted to the developing nervous system (Gad et al, ), neogenin has a much broader expression pattern. Neogenin is found in the dividing neurogenic and gliogenic progenitors as well as maturing neurons throughout the embryonic and adult central nervous system (Vielmetter et al, ; Keeling et al, ; Fitzgerald et al, ; van den Heuvel et al, ). Outside of the nervous system, neogenin is found in many developing and adult tissues, including the gut, heart, kidney, lung, liver, skeletal muscle, and bone (Gad et al, ; Rodriguez et al, ).…”

“…RGMa was the first RGM family member discovered (Monnier et al, 2002), and it has a broad expression pattern during mouse development (Corradini et al, 2009). RGMa is expressed in the central nervous system in a mostly nonoverlapping fashion with RGMb (Oldekamp et al, 2004;Schmidtmer and Engelkamp, 2004;van den Heuvel et al, 2013). It is also expressed in the developing mouse cochlea, lung, limb, and gut (Oldekamp et al, 2004;Metzger et al, 2005).…”

“…It is also expressed in the developing mouse cochlea, lung, limb, and gut (Oldekamp et al, 2004;Metzger et al, 2005). In the adult mouse, RGMa expression is found in the brain, skin, heart, liver, lung, kidney, testis, and gut (Babitt et al, 2005;Metzger et al, 2005;Corradini et al, 2009;van den Heuvel et al, 2013). The broad expression pattern of RGMa in the developing mouse embryo suggests that it plays important roles in development, especially in central nervous system development.…”

Callosal septa express guidance cues and are paramedian guideposts for human corpus callosum development

“…Neogenin was found on several major axon tracts, such as the anterior commissure in the mouse brain (Van den Heuvel et al. ). The ephrin ligands/Eph receptors tyrosine kinases (EphRTK) family of guidance cues regulates neuron migration and guides axons along intermediate choice points, preventing cells and axons from entering inappropriate territories (for reviews see Klein & Kania, ; Kania & Klein, ).…”

Neogenin-YAP signaling in neocortical astrocytic differentiation

“…28,29 By taking advantage of X-gal reporter in neogenin mutant mice and antibodies, we have demonstrated neogenin's expression in embryonic NSCs in vitro and in vivo, 30 in consistent with the previous reports. [31][32][33][34] Neogenin deficient mice or NSCs showed normal self-renewal or proliferation of NSCs or neurogenesis, 30 but impaired neocortical astrogliogenesis. Note that neogenin is reported to regulate adult neurogenesis by promoting neuroblast migration and cell cycle exit, 35 suggesting that neogenin may play an age-dependent function during neurogenesis.…”