The Netrin/RGM Receptor, Neogenin, Controls Adult Neurogenesis by Promoting Neuroblast Migration and Cell Cycle Exit

Abstract

A comprehensive understanding of adult neurogenesis is essential for the development of effective strategies to enhance endogenous neurogenesis in the damaged brain. Olfactory interneurons arise throughout life from stem cells residing in the subventricular zone of the lateral ventricle. Neural precursors then migrate along the rostral migratory stream (RMS) to the olfactory bulb. To ensure a continuous supply of adult-born interneurons, precursor proliferation, migration, and differentiation must be tightly coordinated. Here, we show that the netrin/repulsive guidance molecule receptor, Neogenin, is a key regulator of adult neurogenesis. Neogenin loss-of-function (Neo gt/gt ) mice exhibit a specific reduction in adult-born calretinin interneurons in the olfactory granule cell layer. In the absence of Neogenin, neuroblasts fail to migrate into the olfactory bulb and instead accumulate in the RMS. In vitro migration assays confirmed that Neogenin is required for Netrin-1-mediated neuroblast migration and chemoattraction. Unexpectedly, we also identified a novel role for Neogenin as a regulator of the neuroblast cell cycle. We observed that those neuroblasts able to reach the Neo gt/gt olfactory bulb failed to undergo terminal differentiation. Cell cycle analysis revealed an increase in the number of S-phase neuroblasts within the Neo gt/gt RMS and a significant reduction in the number of neuroblasts exiting the cell cycle, providing an explanation for the loss of mature calretinin interneurons in the granule cell layer. Therefore, Neogenin acts to synchronize neuroblast migration and terminal differentiation through the regulation of neuroblast cell cycle kinetics within the neurogenic microenvironment of the RMS. STEM CELLS 2015;33:503-514

Stroke alters behavior of human skin-derived neural progenitors after transplantation adjacent to neurogenic area in rat brain

“…The same signals that regulate neuronal migration also mediate neurite outgrowth [36]. One example is netrin proteins, which are important regulators of axon guidance and cell migration, and whose receptor is present on neural precursors in the adult mouse and human SVZ and RMS [37]. Also Syndecan-3 has been reported to be crucial for radial migration and neurite outgrowth in the developing brain [38, 39].…”

RGMB and neogenin control cell differentiation in the developing olfactory epithelium

“…Whether these interactions also play a role in the regeneration and maintenance of cell populations in the OE throughout adulthood will have to be addressed in the future using cell-specific temporal ablation of these two proteins in the OE. Furthermore, our results raise the interesting possibility that cell-cell interactions mediated by RGMB and neogenin might also regulate progenitor cell fate choice in other regions of the nervous system, including the ventricular zone of the brain, where neogenin is expressed by a subpopulation of progenitor cells and regulates neuroblast differentiation (Fitzgerald et al, 2006;O'Leary et al, 2015). The floxed Neo1 allele that we have described will be an invaluable tool in the effort to uncover the in vivo functions of neogenin in other regions of the nervous system, as well as in other physiological systems of the developing and adult mouse.…”

“…Furthermore, ablation of RGMB led to increased numbers of dividing progenitor cells without having an effect on the survival of ORNs, supporting a direct effect for RGMB-neogenin signaling in regulating cell cycle progression and exit. Interestingly, reduced neogenin expression also leads to decreased cell cycle exit in neuroblasts of the subventricular zone in adult mice (O'Leary et al, 2015).…”

“…RGMs are GPIanchored proteins widely expressed in the nervous system that can repel axons in a neogenin-dependent fashion (Conrad et al, 2010;Monnier et al, 2002;Oldekamp et al, 2004;O'Leary et al, 2013;Rajagopalan et al, 2004;Tassew et al, 2012;Wilson and Key, 2006). Furthermore, RGM-neogenin signaling has been implicated in the regulation of neuronal differentiation, neural tube closure and neuronal survival (Kee et al, 2008;Koeberle et al, 2010;Matsunaga et al, 2006Matsunaga et al, , 2004O'Leary et al, 2015;Shin and Wilson, 2008).…”

Neogenin-YAP signaling in neocortical astrocytic differentiation

“…[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. Although neogenin is not required for neural differentiation in cultured NSCs and in neonatal age, multiple neogenin mutant mice, including neogenin hypomorphic allele, neogenin Nestin -CKO, and neogenin GFAP -CKO, show an impairment in neocortical, but not hippocampal, astrogliogenesis.…”