NoGo-A and its receptor NgR1 regulate neural stem cell activity and production of new neurons in the adult central nervous system
The protein NoGo-A, originally discovered as a simple myelin component, plays a fundamental role in both restricting growth of aberrant or dysfunctional connections in the mature Central Nervous System (CNS) and in hampering the reconnection of interrupted circuits after damage (Schwab, 2010). Our study published in The Journal of Neuroscience (Rolando et al., 2012) reveals that NoGo-A also limits the production of new neurons by adult neural stem cells, suggesting a key role for this protein and its receptor NgR1 in the maintenance of CNS structural stability.
Studies over the last decades have shown that the mammalian CNS, previously thought to be a ‘perennial’ tissue with no cell renewal, is capable to generate new neurons and glial cells also at adult ages. While production of new glia is rather diffuse in the mature CNS, generation of new neurons (neurogenesis) occurs at restricted sites. One of these is the wall surrounding the later ventricles of the cerebral hemispheres (Subventricular Zone). Here, a cell population resides that shares many features with the type of glial cells called astroglia but, differently from these, proliferate and self-renew throughout the adult life and, via intermediate progenitors, produce new neurons that subsequently migrate to their final destination (Figure 1A). These neurogenic cells are adult neural stem cells.
Our study has demonstrated that NoGo-A and its receptor NgR1 are expressed in the Subventricular Zone neurogenic niche. While NoGo-A is found on young neurons NgR1 is on neural stem cells. By in vitro and in vivo approaches and pharmacological treatments we found that Nogo-A in newly produced neurons exerts a negative control on proliferation and neurogenic activity of neural stem cells via NgR1 (Figure 1B). In addition, independently of NgR1 and via the Rho/ROCK pathway, Nogo-A supports neuroblasts emigration from the niche (Figure 1B), thereby favouring the release of its own inhibition and allowing the reactivation of neurogenic processes. On this basis, we conclude that Nogo-A/NgR1 signalling operates as a homeostatic modulator of the rate of neurogenesis, thereby suggesting a role for this pathway as a universal molecular mediator controlling all forms of neural plasticity.
Our study reveals a novel and unprecedented role for Nogo-A/NgR1 and may have important implications for those CNS pathologies where implementation of endogenous neurogenesis may be stimulated to promote cell replacement after neurodegeneration, and in tumorigenic processes, to counteract the expansion of cancer cells.
Figure 1 (adapted from Rolando et al., 2012)
(A) Schematic drawing of the neurogenic niche of the mouse Subventricular Zone. In tight contact with ependymal cells (gray cells), adult neural stem cells (blue cells) produce new neurons (orange cells) via intermediate progenitors (green cells). (B) NoGo-A expressed by neogenerated neurons activates migration of these cells while, through its interaction with NgR1, inhibits neural stem cell proliferation and neurogenesis.
Schwab M.E. (2010) Functions of Nogo proteins and their receptors in the nervous system. Nat Rev Neurosci 11:799–811.
Rolando C., Parolisi R., Boda E., Schwab M.E., Rossi F., Buffo A. (2012) Distinct roles of nogo-a and nogo receptor 1 in the homeostatic regulation of adult neural stem cell function and neuroblast migration. J Neurosci. 32:17788-99.
Kriegstein A. e Alvarez-Buylla A. (2009) The glial nature of embryonic and adult neural stem cells. Annu Rev Neurosci. 32:149-84.