Age-dependent effect of nitric oxide on subventricular zone and olfactory bulb neural precursor proliferation

Nitric oxide (NO) synthase (NOS) is developmentally regulated in the embryonic brain, where NO participates in cell proliferation, survival, and differentiation. In adults, NO inhibits neurogenesis under physiological conditions. This work investigates whether the NO action is preserved all along development up to adulthood or whether its effects in adults are a new feature acquired during brain maturation. The relationship between nitrergic neurons and precursors, as well as the functional consequences of pharmacological NOS inhibition, were comparatively analyzed in the subventricular zone (SVZ) and olfactory bulb (OB) of postnatal (P7) and adult (>P60) mouse brains. The SVZ was markedly reduced between P7 and adults, and, at both ages, neurons expressing neuronal NOS (nNOS) were found in its striatal limits. In postnatal mice, these nitrergic neurons contained PSA-NCAM, and their projections were scarce, whereas, in adults, mature nitrergic neurons, devoid of PSA-NCAM, presented abundant neuropil. In the OB, local proliferation almost disappeared in the transition to adulthood, and periglomerular nitrergic neurons, some of which were PSA-NCAM positive, were found in postnatal and adult mice. Administration of the NOS inhibitor L-NAME did not affect cell proliferation in the SVZ or in the OB of postnatal mice, whereas it significantly enhanced the number of mitotic cells in both regions in adults. Thus, the NO action on SVZ neurogenesis is a phenomenon that appears after the postnatal age, which is probably due to the germinal layer size reduction, allowing exposure of the NO-sensitive neural precursors to the NO produced in the SVZ-striatum limits.     

Nitric oxide synthesis inhibition increases proliferation of neural precursors isolated from the postnatal mouse subventricular zone

The subventricular zone (SVZ) of rodents retains the capacity to generate new neurons throughout the entire life of the animal. Neural progenitors of the SVZ survive and proliferate in vitro in the presence of epidermal growth factor (EGF). Nitric oxide (NO) has been shown to participate in neural tissue formation during development and to have antiproliferative actions, mediated in part by inhibition of the EGF receptor. Based on these findings, we have investigated the possible effects of endogenously produced and exogenously added NO on SVZ cell proliferation and differentiation. Explants were obtained from postnatal mouse SVZ and cultured in the presence of EGF. Cells migrated out of the explants and proliferated in culture, as assessed by bromodeoxyuridine (BrdU) incorporation. After 72 h in vitro, the colonies formed around the explants were constituted by cells of neuronal or glial lineages, as well as undifferentiated progenitors. Immunoreactivity for the neuronal isoform of NO synthase was observed in neuronal cells with long varicose processes. Cultures treated with the NOS inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) showed an increase in the percentage of BrdU-immunoreactive cells, whereas treatment with the NO donor diethylenetriamine-nitric oxide adduct (DETA-NO) led to a decrease in cell proliferation, without affecting apoptosis. The differentiation pattern was also altered by L-NAME treatment resulting in an enlargement of the neuronal population. The results suggest that endogenous NO may contribute to postnatal neurogenesis by modulating the proliferation and fate of SVZ progenitor cells.     

Identification of first candidate genes for creativity: a pilot study

Nitric oxide (NO) can be neuroprotective or neurotoxic during cerebral ischemia, depending on the NO synthase (NOS) isoform involved. In addition to neurotoxic effect in ischemic brain, inducible NOS (iNOS) also adversely affect ischemic outcome by blocking neurogenesis. In the present study, therefore, we studied the chronological and spatial change of the distribution of iNOS and cell proliferation in subventricular zone (SVZ) after transient focal cerebral ischemia. After 90 min of transient middle cerebral artery occlusion (tMCAO), iNOS-positive cells decreased in the ischemic core at 1 to 21 days, and increased in the ipsilateral periischemic area at 1 and 3 days. 5-Bromodeoxyuridine (BrdU)-positive cells appeared in the ischemic core at 3 to 21 days, appeared in the periischemic area at 3 and 7 days, and increased in the ipsilateral SVZ at 7 days. ED-1-positive cells appeared in the ischemic core at 3 to 21 days, and some of them were double positive with BrdU or iNOS, but the majority were BrdU-negative. The present study suggests that astrocytes are born within the periischemic area at early stage after tMCAO and migrate from SVZ into periischemic area at later stage, and that time-dependent and spatial changes of iNOS expression may be involved in the proliferation and differentiation of adult neurogenesis after focal cerebral ischemia.     

Morphological bases for a role of nitric oxide in adult neurogenesis

The subventricular zone (SVZ) of the adult mouse brain retains the capacity to generate new neurons from stem cells. The neuronal precursors migrate tangentially along the rostral migratory stream (RMS) towards the olfactory bulb, where they differentiate as periglomerular and granular interneurons. In this study, we have investigated whether nitric oxide (NO), a signaling molecule in the nervous system with a role in embryonic neurogenesis, may be produced in the proximity of the progenitor cells in the adult brain, as a prerequisite to proposing a functional role for NO in adult neurogenesis. Proliferating and immature precursor cells were identified by immunohistochemistry for bromo-deoxyuridine (BrdU) and PSA-NCAM, respectively, and nitrergic neurons by either NADPH-diaphorase staining or immunohistochemical detection of neuronal NO synthase (NOS I). Nitrergic neurons with long varicose processes were found in the SVZ, intermingled with chains of cells expressing PSA-NCAM or containing BrdU. Neurons with similar characteristics surrounded the RMS all along its caudo-rostral extension as far as the core of the olfactory bulb. No expression of NOS I by precursor cells was detected either in the proliferation or in the migration zones. Within the olfactory bulb, many small cells in the granular layer and around the glomeruli expressed either PSA-NCAM or NOS I and, in some cases, both markers. Colocalization was also found in a few isolated cells at a certain distance from the neurogenesis areas. The anatomical disposition shown indicates that NO may be released close enough to the neuronal progenitors to allow a functional influence of this messenger in adult neurogenesis.     

Neuronal nitric oxide synthase (NOS-I) knockout increases the survival rate of neural cells in the hippocampus independently of BDNF

Investigations regarding the regulation of adult neurogenesis, i.e., the generation of new neurons from progenitor cells, have revealed a high degree of complexity. Although the pleiotropic messenger molecule nitric oxide (NO) has been suggested to modulate adult neurogenesis, the evidence is inconclusive due to the presence of different NO synthase isoforms in the brain. We therefore investigated whether stem cell proliferation or survival is altered in mice lacking neuronal nitric oxide synthase (NOS-I) or both endothelial and neuronal NOS (NOS-I/-III double knockout). While proliferation of neural stem cells was only numerically, but not significantly increased in NOS-I knockdown animals, the survival of newly formed neurons was substantially higher in NOS-I-deficient mice. In contrast, NOS-I/-III double knockout had significantly decreased survival rates. QRT-PCR in NOS-I-deficient mice revealed neither NOS-III upregulation compensating for the loss of NOS-I, nor alterations in VEGF levels as found in NOS-III-deficient animals. As changes in BDNF expression or protein levels were observed in the cortex, cerebellum and striatum, but not the hippocampus, the increase in stem cell survival appears not to be due to a BDNF mediated mechanism. Finally, NOS-I containing neurons in the dentate gyrus are rare and not localized close to progenitor cells, rendering direct NO effects on these cells unlikely. In conclusion, we suggest that NO predominantly inhibits the survival of new-born cells, by an indirect mechanism not involving BDNF or VEGF. Together, these results emphasize the important role of the different NOS isoforms with respect to adult neurogenesis.     

A diacylglycerol lipase-CB2 cannabinoid pathway regulates adult subventricular zone neurogenesis in an age-dependent manner

The subventricular zone (SVZ) is a major site of neurogenesis in the adult. We now show that ependymal and proliferating cells in the adult mouse SVZ express diacylglycerol lipases (DAGLs), enzymes that synthesise a CB1/CB2 cannabinoid receptor ligand. DAGL and CB2 antagonists inhibit the proliferation of cultured neural stem cells, and the proliferation of progenitor cells in young animals. Furthermore, CB2 agonists stimulate progenitor cell proliferation in vivo, with this effect being more pronounced in older animals. A similar response was seen with a fatty acid amide hydrolase (FAAH) inhibitor that limits degradation of endocannabinoids. The effects on proliferation were mirrored in changes in the number of neuroblasts migrating from the SVZ to the olfactory bulb (OB). In this context, CB2 antagonists reduced the number of newborn neurons appearing in the OB in the young adult animals while CB2 agonists stimulated this in older animals. These data identify CB2 receptor agonists and FAAH inhibitors as agents that can counteract the naturally observed decline in adult neurogenesis that is associated with ageing.     

Striatal deafferentation increases dopaminergic neurogenesis in the adult olfactory bulb

Dopaminergic loss is known to be one of the major hallmarks of Parkinson disease (PD). In addition to its function as a neurotransmitter, dopamine plays significant roles in developmental and adult neurogenesis. Both dopaminergic deafferentation and stimulation modulate proliferation in the subventricular zone (SVZ)/olfactory bulb system as well as in the hippocampus. Here, we study the impact of 6-hydroxydopamine (6-OHDA) lesions to the medial forebrain bundle on proliferation and neuronal differentiation of newly generated cells in the SVZ/olfactory bulb axis in adult rats. Proliferation in the SVZ decreased significantly after dopaminergic deafferentation. However, the number of neural progenitor cells expressing the proneuronal cell fate determinant Pax-6 increased in the SVZ. Survival and quantitative cell fate analysis of newly generated cells revealed that 6-OHDA lesions induced opposite effects in the two different regions of neurogenesis in the olfactory bulb: a transient decrease in the granule cell layer contrasts to a sustained increase of newly generated neurons in the glomerular layer. These data point towards a shift in the ratio of newly generated interneurons in the olfactory bulb layers. Dopaminergic neurogenesis in the glomerular layer tripled after lesioning and consistent with this finding, the total number of tyrosine hydroxylase (TH)-positive cells increased. Thus, loss of dopaminergic input to the SVZ led to a distinct cell fate decision towards stimulation of dopaminergic neurogenesis in the olfactory bulb glomerular layer. This study supports the accumulating evidence that neurotransmitters play a crucial role in determining survival and differentiation of newly generated neurons.     

Phenytoin enhances the phosphorylation of epidermal growth factor receptor and fibroblast growth factor receptor in the subventricular zone and promotes the proliferation of neural precursor cells and oligodendrocyte differentiation

Phenytoin is a widely used antiepileptic drug that induces cell proliferation in several tissues, such as heart, bone, skin, oral mucosa and neural precursors. Some of these effects are mediated via fibroblast growth factor receptor (FGFR) and epidermal growth factor receptor (EGFR). These receptors are strongly expressed in the adult ventricular–subventricular zone (V‐SVZ), the main neurogenic niche in the adult brain. The aim of this study was to determine the cell lineage and cell fate of V‐SVZ neural progenitors expanded by phenytoin, as well as the effects of this drug on EGFR/FGFR phosphorylation. Male BALB/C mice received 10 mg/kg phenytoin by oral cannula for 30 days. We analysed the proliferation of V‐SVZ neural progenitors by immunohistochemistry and western blot. Our findings indicate that phenytoin enhanced twofold the phosphorylation of EGFR and FGFR in the V‐SVZ, increased the number of bromodeoxyuridine (BrdU)+/Sox2+ and BrdU+/doublecortin+ cells in the V‐SVZ, and expanded the population of Olig2‐expressing cells around the lateral ventricles. After phenytoin removal, a large number of BrdU+/Receptor interacting protein (RIP)+ cells were observed in the olfactory bulb. In conclusion, phenytoin enhanced the phosphorylation of FGFR and EGFR, and promoted the expression of neural precursor markers in the V‐SVZ. In parallel, the number of oligodendrocytes increased significantly after phenytoin removal.     

Calorie restriction activates new adult born olfactory‐bulb neurones in a ghrelin‐dependent manner but acyl‐ghrelin does not enhance subventricular zone neurogenesis

The ageing and degenerating brain show deficits in neural stem/progenitor cell (NSPC) plasticity that are accompanied by impairments in olfactory discrimination. Emerging evidence suggests that the gut hormone ghrelin plays an important role in protecting neurones, promoting synaptic plasticity and increasing hippocampal neurogenesis in the adult brain. In the present study, we investigated the role of ghrelin with respect to modulating adult subventricular zone (SVZ) NSPCs that give rise to new olfactory bulb (OB) neurones. We characterised the expression of the ghrelin receptor, growth hormone secretagogue receptor (GHSR), using an immunohistochemical approach in GHSR‐eGFP reporter mice to show that GHSR is expressed in several regions, including the OB but not in the SVZ of the lateral ventricle. These data suggest that acyl‐ghrelin does not mediate a direct effect on NSPC in the SVZ. Consistent with these findings, treatment with acyl‐ghrelin or genetic silencing of GHSR did not alter NSPC proliferation within the SVZ. Similarly, using a bromodeoxyuridine pulse‐chase approach, we show that peripheral treatment of adult rats with acyl‐ghrelin did not increase the number of new adult‐born neurones in the granule cell layer of the OB. These data demonstrate that acyl‐ghrelin does not increase adult OB neurogenesis. Finally, we investigated whether elevating ghrelin indirectly, via calorie restriction (CR), regulated the activity of new adult‐born cells in the OB. Overnight CR induced c‐Fos expression in new adult‐born OB cells but not in developmentally born cells, whereas neuronal activity was absent following re‐feeding. These effects were not present in ghrelin^?/? mice, suggesting that adult‐born cells are uniquely sensitive to changes in ghrelin mediated by fasting and re‐feeding. In summary, ghrelin does not promote neurogenesis in the SVZ and OB; however, new adult‐born OB cells are activated by CR in a ghrelin‐dependent manner.     

Chronic inhibition of nitric oxide synthesis enhances both subventricular zone neurogenesis and olfactory learning in adult mice

The ability to generate new neurons during the course of adult life is preserved in the subventricular zone of the lateral ventricles and the dentate gyrus of the hippocampus in the mammalian brain. These two regions constitute specifically regulated neurogenic niches, and provide newborn neurons involved in olfactory and spatial learning, respectively. Nitric oxide (NO) is a negative regulator of neurogenesis in the subventricular zone, whereas its role in the dentate gyrus remains controversial. Using systemic administration of NO synthase (NOS) inhibitors to chronically inhibit NO production, we increased neural precursor proliferation in the subventricular zone as well as neurogenesis in the olfactory bulb, without modifying the number of mitotic cells or the granular cell layer thickness in the dentate gyrus. The same treatment specifically improved olfactory learning performance, whereas spatial learning and memory was unchanged, thus demonstrating that olfactory memory is closely associated with the level of ongoing neurogenesis in the subventricular zone-olfactory bulb. The anatomical specificity of the NOS inhibitor actions was not due to differences in the availability of NO, as demonstrated by immunohistochemical detection of neuronal NOS and S-nitrosylated proteins in both regions. Remarkably, the distinct NO sensitivity might result from a differential expression of epidermal growth factor receptor in precursor cells in both regions, as the proliferative effect of NOS inhibitors in the subventricular zone was restricted to the cells that expressed this receptor.     

Induction of neurogenesis in the adult rat subventricular zone and neostriatum following dopamine D3 receptor stimulation

Discrete regions of the adult CNS, including the subventricular zone (SVZ), do retain the capacity for neurogenesis. These progenitor cells may represent a potential new source of cells for replacement therapies in neuroregenerative diseases. An understanding of the microenvironmental signals regulating neurogenesis in the adult brain would facilitate the development of such therapeutic approaches. A particularly strong expression of dopamine D(3) receptor mRNA occurs in the proliferative SVZ during prenatal and early postnatal ontogeny. Although its expression diminishes following development, a restricted D(3) receptor expression persists in this region through adulthood, coincident with continued proliferation in this region. Here, we demonstrate a two-fold induction of cell proliferation (BrdU incorporation) in the SVZ and rostral migratory stream of the adult Sprague-Dawley rat brain following intrasubventricular administration of the dopamine D(3) receptor agonist, 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) for 2 weeks. The number of BrdU-positive cells was elevated ten-fold from very low baseline levels in the neighbouring neostriatum, another region known to express D(3) receptors. These striatal BrdU-positive cells appeared within 3 days following intracerebral infusion of 7-OH-DPAT and were distributed homogeneously throughout the striatum following systemic administration. This suggests that these cells originate from resident progenitor cells rather than the SVZ. Dopamine D(3) receptor activation may serve as a proneuronal differentiation signal as 60-70% of the new cells had neuronal markers following 7-OH-DPAT infusion. These results suggest that the dopamine D(3) receptor may be a good drug target for cell replacement strategies, particularly because of the fact that its expression is almost exclusively limited to the nervous system.     

Rat forebrain neurogenesis and striatal neuron replacement after focal stroke

The persistence of neurogenesis in the forebrain subventricular zone (SVZ) of adult mammals suggests that the mature brain maintains the potential for neuronal replacement after injury. We examined whether focal ischemic injury in adult rat would increase SVZ neurogenesis and direct migration and neuronal differentiation of endogenous precursors in damaged regions. Focal stroke was induced in adult rats by 90-minute right middle cerebral artery occlusion (tMCAO). Cell proliferation and neurogenesis were assessed with bromodeoxyuridine (BrdU) labeling and immunostaining for cell type-specific markers. Brains examined 10-21 days after stroke showed markedly increased SVZ neurogenesis and chains of neuroblasts extending from the SVZ to the peri-infarct striatum. Many BrdU-labeled cells persisted in the striatum and cortex adjacent to infarcts, but at 35 days after tMCAO only BrdU-labeled cells in the neostriatum expressed neuronal markers. Newly generated cells in the injured neostriatum expressed markers of medium spiny neurons, which characterize most neostriatal neurons lost after tMCAO. These findings indicate that focal ischemic injury increases SVZ neurogenesis and directs neuroblast migration to sites of damage. Moreover, neuroblasts in the injured neostriatum appear to differentiate into a region-appropriate phenotype, which suggests that the mature brain is capable of replacing some neurons lost after ischemic injury.     

Evidence for constitutive neural cell proliferation in the adult murine hypothalamus

Compelling evidence suggests that the mammalian brain is capable of generating new neurons throughout adult life. While neurogenesis can be induced at various brain sites by exogenous cues, constitutive birth of new neurons has been unambiguously demonstrated within the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus. The lack of strong evidence that constitutive neurogenesis occurs elsewhere in the adult brain could be due to its exclusive restriction to the SVZ and SGZ or, for instance, to the inadequacy of the methods used to reveal new-born neurons at other brain sites. By using intracerebroventricular (icv) delivery of the mitotic marker bromodeoxyuridine (BrdU) we demonstrate that new cells are born continuously and in substantial numbers in the adult murine hypothalamus and that many of these cells appear to differentiate into neurons as assessed by the expression of doublecortin (Dcx) and other neuronal fate markers. As compared to intraperitoneal (ip) BrdU injections, central BrdU infusion also uncovers a higher-fold induction of hypothalamic cell proliferation by ciliary neurotrophic factor (CNTF). It appears that new cells are born throughout the hypothalamic parenchyma without an apparent restriction to a specific neurogenic layer, as seen in the SVZ. Thus, we provide evidence that the adult hypothalamus is constitutively neurogenic and that hypothalamic cell proliferation is highly responsive to mitogen action.     

The FGF-2/FGFRs neurotrophic system promotes neurogenesis in the adult brain

Neurogenesis occurs in two regions of the adult brain, namely, the subventricular zone (SVZ) throughout the wall of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus (DG) in hippocampal formation. Adult neurogenesis requires several neurotrophic factors to sustain and regulate the proliferation and differentiation of the adult stem cell population. In the present review, we examine the cellular and functional aspects of a trophic system mediated by fibroblast growth factor-2 (FGF-2) and its receptors (FGFRs) related to neurogenesis in the SVZ and SGZ of the adult rat brain. In the SVZ, FGF-2 is expressed in GFAP-positive cells of SVZ but is not present in proliferating precursor cells, which instead express FGFR-1 and FGFR-2, but not FGFR-3 mRNA, although expressed in the SVZ, and FGFR-4. Therefore, it seems that in the SVZ FGF-2 may be released by GFAP-positive cells, different from the precursor cell lineage, and via volume transmission it reaches the proliferating precursor cells. FGFR-1 mRNA is also expressed in the SGZ and is localized in BrdU-labeled precursor cells, whereas FGFR-2 and FGFR-3 mRNA, although expressed in the SGZ, are not located within proliferating precursor cells. An aged-related decline of proliferating precursor cells in the SVZ and DG of old rats has been well documented, and there is the suggestion that in part it could be the consequence of alterations in growth factor expression levels. Thus, the old precursors may respond to growth factors, suggesting that during aging the basic components for neuronal precursor cell proliferation are retained and the capacity to increase neurogenesis after appropriate stimulation is still preserved. In conclusion, the trophic system mediated by FGF-2 and its receptors contributes to create an important micro-environmental niche that promotes neurogenesis in the adult and aged brain. This article is dedicated to the special issue Brain Plasticity: Aging and Neuropychiatric Disorders.     

Endogenous and exogenous ciliary neurotrophic factor enhances forebrain neurogenesis in adult mice

Neurogenesis in the adult mammalian CNS occurs in the subventricular zone (SVZ) and dentate gyrus. The receptor for ciliary neurotrophic factor (CNTF), CNTFRalpha, is expressed in the adult subventricular zone. Because the in vitro effects of CNTF on neural precursors have been varied, including proliferation and differentiation into neurons or glia, we investigated its role in vivo. Injection of CNTF in the adult C57BL/6 mice forebrain increased the number of cells labeled with ip BrdU in both neurogenic regions. In the dentate gyrus, CNTF also appeared to enhance differentiation of precursors into neurons, i.e., increased the proportion of NeuN+/BrdU+ cells from approximately 14 to approximately 29%, but did not affect differentiation into astrocytes (GFAP+) or oligodendrocytes (CNPase+). In the SVZ, CNTF increased the proportion of GFAP+/BrdU+ cells from approximately 1 to approximately 2%. CNTF enhanced the distance of migration of new neurons into the granule cell layer. Intraventricular injection of neutralizing anti-CNTF antibodies reduced the number of BrdU-labeled cells in the SVZ. These results suggest that endogenous CNTF regulates adult neurogenesis by increasing proliferation of neural stem cells and/or precursors. Alternatively, CNTF could maintain cells longer in the S-phase, resulting in increased BrdU labeling. In the neurogenic region of the SVZ, CNTFRalpha was exclusively present in GFAP-positive process-bearing cells, suggesting that CNTF affects neurogenesis indirectly via neighboring astroglia. Alternatively, these cells may be part of the neural precursor lineage. The restricted expression of CNTF within the nervous system makes it a potential selective drug target for cell replacement strategies.     

Neonatal hypoxic-ischemic injury increases forebrain subventricular zone neurogenesis in the mouse

Neurogenesis persists throughout life in the rodent subventricular zone (SVZ)-olfactory bulb pathway and increases in the adult after brain insults. The influence of neonatal injury on SVZ neural precursors is unknown. We examined the effects of hypoxia-ischemia (HI) on neonatal mouse SVZ cell proliferation and neurogenesis. Postnatal day 10 (P10) mice underwent right carotid artery ligation followed by 10% O2 exposure for 45 min. The SVZ area and hemispheric injury were quantified morphometrically 1-3 weeks later. Bromodeoxyuridine (BrdU) was used to label proliferating cells, and cell phenotypes of the progeny were identified by immunohistochemistry. HI significantly enlarged the ipsilateral SVZ at P18, P24, and P31, and increases in the SVZ area correlated directly with the degree of hemispheric damage. HI also stimulated cell proliferation and neurogenesis in the SVZ and peri-infarct striatum. Some newborn cells expressed a neuronal phenotype at P24, but not at P31, indicating that neurogenesis was short-lived. These results suggest that augmenting SVZ neuroblast recruitment and survival may improve neural repair after neonatal brain injury.     

Ultrastructural and antigenic properties of neural stem cells and their progeny in adult rat subventricular zone

Neural stem cells (NSCs) in the subventricular zone (SVZ) continuously generate olfactory bulb interneurons in the adult rodent brain. Based on their ultrastructural and antigenic properties, NSCs, transient amplifying precursor cells, and neuroblasts (B, C, and A cells, respectively) have been distinguished in mouse SVZ. Here, we aimed to identify these cell types in rat SVZ ultrastructurally and at the light microscopy level, and to determine the antigenic properties of each cell type using gold and fluorescence immunolabeling. We found astrocytes with single cilia (NSCs, correspond to B cells) and neuroblasts (A cells). We also observed mitotic cells, ependymal cells, displaced ependymal cells, and mature astrocytes. In contrast, transient amplifying precursor cells (C cells) were not detected. The NSCs and neuroblasts had epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor alpha (PDGFRalpha) expressed on the ciliary apparatus and were the only cell types incorporating the proliferation marker BrdU. Throughout mitosis, EGFR and PDGFRalpha were associated with the microtubule of the mitotic spindle. Ependymal and displaced ependymal cells also expressed EGFR and PDGFRalpha on their cilia but did not incorporate BrdU. Our findings indicate that the NSCs in adult rat SVZ give rise directly to neuroblasts. During mitosis, the NSCs disassemble the primary cilium and symmetrically distribute EGFR and PDGFRalpha among their progeny.     

Meteorin is a chemokinetic factor in neuroblast migration and promotes stroke-induced striatal neurogenesis

Ischemic stroke affecting the adult brain causes increased progenitor proliferation in the subventricular zone (SVZ) and generation of neuroblasts, which migrate into the damaged striatum and differentiate to mature neurons. Meteorin (METRN), a newly discovered neurotrophic factor, is highly expressed in neural progenitor cells and immature neurons during development, suggesting that it may be involved in neurogenesis. Here, we show that METRN promotes migration of neuroblasts from SVZ explants of postnatal rats and stroke-subjected adult rats via a chemokinetic mechanism, and reduces N-methyl-D-asparate-induced apoptotic cell death in SVZ cells in vitro. Stroke induced by middle cerebral artery occlusion upregulates the expression of endogenous METRN in cells with neuronal phenotype in striatum. Recombinant METRN infused into the stroke-damaged brain stimulates cell proliferation in SVZ, promotes neuroblast migration, and increases the number of immature and mature neurons in the ischemic striatum. Our findings identify METRN as a new factor promoting neurogenesis both in vitro and in vivo by multiple mechanisms. Further work will be needed to translate METRN's actions on endogenous neurogenesis into improved recovery after stroke.