Characterization of the Netrin/RGMa receptor neogenin in neurogenic regions of the mouse and human adult forebrain

Abstract

In the adult rodent forebrain, astrocyte-like neural stem cells reside within the subventricular zone (SVZ) and give rise to progenitors and neuroblasts, which then undergo chain migration along the rostral migratory stream (RMS) to the olfactory bulb, where they mature into fully functional interneurons. Neurogenesis also occurs in the adult human SVZ, where neural precursors similar to the rodent astrocyte-like stem cell and neuroblast have been identified. A migratory pathway equivalent to the rodent RMS has also recently been described for the human forebrain. In the embryo, the guidance receptor neogenin and its ligands netrin-1 and RGMa regulate important neurogenic processes, including differentiation and migration. We show in this study that neogenin is expressed on neural stem cells (B cells), progenitor cells (C cells), and neuroblasts (A cells) in the adult mouse SVZ and RMS. We also show that netrin-1 and RGMa are ideally placed within the neurogenic niche to activate neogenin function. Moreover, we find that neogenin and RGMa are also present in the neurogenic regions of the human adult forebrain. We show that neogenin is localized to cells displaying stem cell (B cell)-like characteristics within the adult human SVZ and RMS and that RGMa is expressed by the same or a closely apposed cell population. This study supports the hypothesis that, as in the embryo, neogenin regulates fundamental signalling pathways important for neurogenesis in the adult mouse and human forebrain.

Netrin 1 contributes to vascular remodeling in the subventricular zone and promotes progenitor emigration after demyelination

“…We found DCC and neogenin expression in the adult SVZ, in agreement with a previous study (Bradford et al, 2010), but almost undetectable levels of UNC5, which is the main receptor responsible for NTN1 repulsion effects (Bradford et al, 2009). This receptor expression pattern is therefore not favorable to the repulsive hypothesis.…”

“…Furthermore, NTN1 and its receptors have recently been detected in postnatal SVZ and RMS (Bradford et al, 2010;Hakanen et al, 2011). Here, we observed by western blot very low NTN1 expression in the SVZ of adult healthy mice but a strong and significant increase in SVZ a few days after CC demyelination.…”

Gene expression changes consistent with neuroAIDS and impaired working memory in HIV-1 transgenic rats

“…Mice that lack the ErbBs with intrinsic tyrosine kinase activity (ErbB2 and ErbB4) in the CNS have reduced dendritic spine density and behavioral abnormalities [53], possibly implicating this ErbB signaling in synaptodendritic injury. Netrins are secreted mediators that exert multiple trophic actions including axon guidance [70], synaptic plasticity [71], prevention of apoptosis [72,73], adult neurogenesis including in the course of CNS regeneration [74-76], which is believed to be impaired in neuroAIDS [77], and synaptic trophism [54]. …”

Role of netrin-1 in the organization and function of the mesocorticolimbic dopamine system

“…75 Neogenin, a second member of the DCC family in the vertebrate, is another netrin-1 receptor that appears to be involved in neurogenesis in the developing and adult brain. 76 Expression of these netrin-1 receptors by DA neurons remains to be determined. Similarly, it is important to clarify that the role of netrin-1 is not restricted to neuronal connectivity, but also involves cell adhesion, cell migration, cell death and angiogenesis processes (for reviews see Bradford and colleagues, 62 Baker and colleagues, 77 Mehlen and Guenubeaud 78 and Castets and Mehlen 79 ).…”