Retinoic acid regulates postnatal neurogenesis in the murine subventricular zone-olfactory bulb pathway

Abstract

Neurogenesis persists throughout life in the rodent subventricular zone (SVZ)-olfactory bulb pathway. The molecular regulation of this neurogenic circuit is poorly understood. Because the components for retinoid signaling are present in this pathway, we examined the influence of retinoic acid (RA) on postnatal SVZ-olfactory bulb neurogenesis. Using both SVZ neurosphere stem cell and parasagittal brain slice cultures derived from postnatal mouse, we found that RA exposure increased neurogenesis by enhancing the proliferation and neuronal differentiation of forebrain SVZ neuroblasts. The RA precursor retinol had a similar effect, which was reversed by treating cultures with the RA synthesis inhibitor disulfiram. Electroporation of dominant-negative retinoid receptors into the SVZ of slice cultures also blocked neuroblast migration to the olfactory bulb and altered the morphology of the progenitors. Moreover, the administration of disulfiram to neonatal mice decreased in vivo cell proliferation in the striatal SVZ. These results indicate that RA is a potent mitogen for SVZ neuroblasts and is required for their migration to the olfactory bulb. The regulation of multiple steps in the SVZ-olfactory bulb neurogenic pathway by RA suggests that manipulation of retinoid signaling is a potential therapeutic strategy to augment neurogenesis after brain injury.

Effects of retinoic acid on ischemic brain injury-induced neurogenesis

“…Effects of disulfiram, an inhibitor of endogenous RA synthesis, were consistent with the previous report (Wang et al, 2005), although this result was against our conclusion. However many other effects of disulfiram have been reported.…”

“…For example, in neural stem cell cultures isolated from the embryonic striatal SVZ or adult hippocampus, RA exposure stimulates neurogenesis (Wohl and Weiss, 1998;Takahashi et al, 1999). Moreover, in SVZ neurosphere stem cell and parasagittal brain slice cultures derived from postnatal mouse, RA exposure increased neurogenesis by enhancing the proliferation and neuronal differentiation of forebrain SVZ neuroblasts (Wang et al, 2005). Furthermore, prolonged oral RA administration also increases adult rat SVZ cell proliferation (Giardino et al, 2000).…”

“…RA exposure stimulates neurogenesis in neural stem cell cultures isolated from the embryonic striatal SVZ or adult hippocampus (Wohl and Weiss, 1998;Wang et al, 2005). Moreover, prolonged oral RA administration also increases adult rat SVZ cell proliferation (Giardino et al, 2000).…”

Retinoic-Acid-Induced Downregulation of the 67 KDa Laminin Receptor Correlates with Reduced Biological Aggressiveness of Human Neuroblastoma Cells

“…Similar RA-induced rapid transient increases in migration and invasion in neuroblastoma cells have been reported (Joshi et al, 2006;Meseguer et al, 2011), and correlated to the expression of tissue transglutaminase (Joshi et al, 2006). Blocking of RA signaling in vivo also impaired neuroblast migration from the subventricular zone of the brain to the olfactory bulb (Wang et al, 2005a), suggesting that short term RA-induced increases in migration probably reflects a physiological feature of RA action on the regulation of neurogenesis. Coupling of differentiation with migration has been described for mouse cortical neurons and the involvement of proneural bHLHs transcription factors in migration has been proposed (Ge et al, 2006).…”

Blue light potentiates neurogenesis induced by retinoic acid-loaded responsive nanoparticles

“…Depletion of RA in adult mice leads to decreased neuronal differentiation and cell survival within the subgranular zone of the hippocampus [8]. Similarly, administration of an inhibitor of RA synthesis (disulfiram) to neonatal mice decreased cell proliferation in the SVZ, and electroporation of dominant-negative RA receptors altered the morphology of neuronal progenitors and blocked neuroblast migration [9]. Importantly, defective RA signalling has been implicated in the onset of brain diseases [10,11].…”