Distinct Roles of Nogo-A and Nogo Receptor 1 in the Homeostatic Regulation of Adult Neural Stem Cell Function and Neuroblast Migration

Abstract

In the adult mammalian subventricular zone (SVZ), GFAP-positive neural stem cells (NSCs) generate neuroblasts that migrate tangentially along the rostral migratory stream (RMS) toward the olfactory bulb (OB). In the mouse brain, we found that the plasticity inhibitors Nogo-A and Nogo receptor 1 (NgR1) are differentially expressed in the SVZ-OB system, in which Nogo-A identifies immature neuroblasts and NgR1 germinal astrocytes. We therefore examined the role of Nogo-A and NgR1 in the regulation of neurogenesis. Pharmacological experiments show that Nogo-66/NgR1 interaction reduces the proliferation of NSCs. This is consistent with a negative-feedback loop, in which newly generated neurons modulate cell division of SVZ stem cells. Moreover, the Nogo-A-⌬20 domain promotes neuroblast migration toward the OB through activation of the Rho/ROCK (Rho-associated, coiled-coil containing protein kinase) pathway, without the participation of NgR1. Our findings reveal a new unprecedented function for Nogo-A and NgR1 in the homeostatic regulation of the pace of neurogenesis in the adult mouse SVZ and in the migration of neuroblasts along the RMS.

New Insights into the Roles of Nogo-A in CNS Biology and Diseases

“…What happened at the motor cortex may be similar with that happened at the cerebral cortex, and a cohort of laterborn neurons migrate past their predecessors to take a more superficial position within the cortical plate (CP), making an ''inside-out'' neuronal distribution pattern, just like climbing on one's body to get to a higher place [5,68,69]. All above demonstrate that Nogo-A's effect on the neuron migration might be induced by Nogo-A-D20 through Rho/ ROCK pathway without the help of NgR1 [18,58].…”

“…Secondly, 1 nM Nogo-66 can induce significant growth cone collapse, but 1 nM D20 can not, which corresponds with the higher specific activity of Nogo-66 for growth cone collapse than D20 [15]. Furthermore, Nogo-66's interaction with NgR1 reduces the proliferation of GFAP-positive neural stem cells (NSCs) potentially through the pathways mentioned above [58].…”

Tetraspanin-3 is an organizer of the multi-subunit Nogo-A signaling complex

“…In vivo, full-length Nogo-A might undergo transcytosis or proteolytic cleavage, resulting in the release of active fragments such as Nogo-A-Δ20 (Joset et al, 2010;Kempf et al, 2014;Thiede-Stan and Schwab, 2015). In the developing CNS, Nogo-A-Δ20 promotes the migration of neuronal precursors but inhibits primary brain microvascular endothelial cell migration, as well as the spreading of endothelial cells and fibroblasts (Kempf et al, 2014;Mathis et al, 2010;Oertle et al, 2003;Rolando et al, 2012;Schmandke et al, 2013;Walchli et al, 2013). Although Nogo-A-Δ20 and Nogo-66 signal through different receptors, the activation of RhoA is a common intracellular signal step downstream of both inhibitory domains (Joset et al, 2010;Kempf et al, 2014;Montani et al, 2009;Nash et al, 2009).…”

The neurite growth inhibitory protein Nogo-A has diverse roles in adhesion and migration

“…The latter is achieved via activation of the RhoA-ROCK pathway without requiring the Nogo-66 receptor NgR1. 7 Also, embryonic neuronal precursors from the cortex of Nogo-A-null mice as well as neurospheres derived from wild-type mice treated with anti-Nogo-A, anti-Lingo-1, or anti-NgR antibodies showed decreased adhesion and increased motility in vitro. 8 Furthermore, BrdU pulse experiments revealed a delay in the tangential migration of E12.5 cortical neurons from Nogo-A/B/ C-null mice in vivo, 9 as well as radial migration defects of neuronal precursors in the cortex of Nogo-A-null vs wild-type mice.…”

“…6 In an entirely different system, the rostral migratory stream in the adult mouse brain, Nogo-A was shown to be expressed in immature neuroblasts while NgR1 was found in germinal astrocytes. 7 Interestingly, the Nogo-66/NgR1 interaction reduces proliferation of the neural stem cells, while the Nogo-A-Δ20 domain promotes migration of the neuroblasts toward the olfactory bulb. The latter is achieved via activation of the RhoA-ROCK pathway without requiring the Nogo-66 receptor NgR1.…”