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.
Highlights
The mammalian nervous system is composed of millions of neurons that are connected through dendritic and axonal processes
Three different timepoints were selected for these studies: E16.5, as an early timepoint during which developmental processes such as neurogenesis, cell migration and axon guidance occur; postnatal day (P)5, characterized by late developmental processes such as synapse formation, pruning and apoptosis; and adulthood, to explore a possible role for repulsive guidance molecules (RGMs)-Neogenin signaling in the plasticity of mature neuronal networks
The specificity of the observed expression patterns could be discerned from the various controls that were included and from the clearly distinct expression patterns
Summary
The mammalian nervous system is composed of millions of neurons that are connected through dendritic and axonal processes. The formation of this exquisitely complex neuronal network is dependent on a precisely ordered series of developmental events including neurogenesis, neuronal differentiation and migration, neurite growth and guidance, and apoptosis. RGMa and RGMb, but not RGMc, are expressed in the nervous system and can act as growth cone collapse factors and repulsive axon guidance cues for different populations of neurons [6,8,9,11,12,13,14,15,16,17,18,19,20–22]
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