Morphological bases for a role of nitric oxide in adult neurogenesis11Published on the World Wide Web on 25 May 2000.

Moreno‐López, Bernardo; Noval, Jose Angel; González-Bonet, Luis Germán; Estrada, Carmen

doi:10.1016/s0006-8993(00)02474-4

Cited by 102 publications

(98 citation statements)

References 33 publications

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“…Our observations that NOS ϩ neurons are largely excluded from the neurogenic areas of the adult rat brain confirm previous findings in mouse (30,31) and are consistent with the notion of paracrine signaling. NO may be produced in the layers adjacent to the dividing cells or may be released from the processes of nitrergic neurons within the SVZ and the RMS.…”

Section: Discussionsupporting

confidence: 92%

Nitric oxide negatively regulates mammalian adult neurogenesis

Packer

Stasiv

Benraiss

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

296

261

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Neural progenitor cells are widespread throughout the adult central nervous system but only give rise to neurons in specific loci. Negative regulators of neurogenesis have therefore been postulated, but none have yet been identified as subserving a significant role in the adult brain. Here we report that nitric oxide (NO) acts as an important negative regulator of cell proliferation in the adult mammalian brain. We used two independent approaches to examine the function of NO in adult neurogenesis. In a pharmacological approach, we suppressed NO production in the rat brain by intraventricular infusion of an NO synthase inhibitor. In a genetic approach, we generated a null mutant neuronal NO synthase knockout mouse line by targeting the exon encoding active center of the enzyme. In both models, the number of new cells generated in neurogenic areas of the adult brain, the olfactory subependyma and the dentate gyrus, was strongly augmented, which indicates that division of neural stem cells in the adult brain is controlled by NO and suggests a strategy for enhancing neurogenesis in the adult central nervous system. T he vast majority of neurons in the mammalian brain are produced during embryonic development. However, remnants of the germinal zones of the developing brain continue to proliferate into adulthood, generating large numbers of neurons in the adult brain (1-3). The subventricular zone (SVZ) of the lateral ventricles (LVs), its anterior extension, the rostral migratory stream (RMS), and the subgranular cell layer (S-GCL) of the dentate gyrus (DG) of the hippocampus are the major sites of adult neurogenesis, although other regions of the adult brain retain the potential to generate new neurons (4-6). Many of the newly generated neurons undergo physiological cell death (7), but it is becoming clear that some of these new neurons become integrated into existing neuronal circuits, thus potentially contributing to a previously unanticipated form of neuroplasticity (8). Several protein growth factors have been shown to affect adult neurogenesis in vivo (5, 6, 9-11). However, the signaling systems involved in regulating cell division in the adult brain are only beginning to be understood.Increasingly diverse functions of NO, a transcellular signaling molecule (12), are continuing to be demonstrated, and there is growing evidence that NO may be involved in controlling proliferation of neuronal cells. Neuronal NO synthase (nNOS), the major NOS isoform in the mammalian brain, is transiently expressed in the developing brain in a pattern suggesting its involvement in neural development (13). Furthermore, NO has been shown to effectively and reversibly suppress cell division (14, 15); this property of NO, coupled to its ability to regulate gene expression, is exploited in a number of developmental contexts (16). Materials and MethodsA full description of the methods used in this work can be found in Supporting Materials and Methods, which is published as supporting information on the PNAS web site, www.pnas.org.All a...

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Section: Discussionsupporting

confidence: 92%

Nitric oxide negatively regulates mammalian adult neurogenesis

Packer

Stasiv

Benraiss

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

296

261

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“…Endogenous NO did not affect survival or migration of SVZ postmitotic cells but contributed to the differentiation of newly arrived neurons in the OB The presence of nitrergic neurons in the proximity of neuroblast chains in the RMS and in the core of the OB (Moreno-Ló pez et al, 2000) suggests that NO might be implicated in cell migration in the adult brain, as reported during development (Tanaka et al, 1994;Contestabile, 2000). However, NOS inhibition did not modify the distribution of postmitotic cells at any time studied after BrdU injections.…”

Section: Phenotypic Characteristics Of No-sensitive Cellsmentioning

confidence: 71%

“…Nitrergic neurons participate in specific sensory motor functions (Moreno-Ló pez et al, 1996), synaptic formation and remodeling (Holscher, 1997), control of cerebral blood flow (Estrada et al, 1993;Iadecola, 1993), and postischemic neuroprotection and neurotoxicity (Estrada and de Felipe, 1998). We have recently shown that in the adult mouse brain, the SVZ is surrounded by differentiated neurons expressing nNOS; these neurons project rich axonal networks in which SVZ neuroblasts are immersed (Moreno-Ló pez et al, 2000). In addition, some neuroblasts contain nNOS once they reach the OB periglomerular area (Moreno-Ló pez et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…We have recently shown that in the adult mouse brain, the SVZ is surrounded by differentiated neurons expressing nNOS; these neurons project rich axonal networks in which SVZ neuroblasts are immersed (Moreno-Ló pez et al, 2000). In addition, some neuroblasts contain nNOS once they reach the OB periglomerular area (Moreno-Ló pez et al, 2000). The spatial proximity between precursor cells and potential NO sources raises the question of whether NO may be one of the factors controlling neurogenesis in the adult brain.…”

Section: Introductionmentioning

confidence: 99%

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Nitric Oxide Is a Physiological Inhibitor of Neurogenesis in the Adult Mouse Subventricular Zone and Olfactory Bulb

Moreno‐López¹,

Romero‐Grimaldi²,

Noval³

et al. 2004

J. Neurosci.

211

188

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The subventricular zone of the rodent brain retains the capacity of generating new neurons in adulthood. The newly formed neuroblasts migrate rostrally toward the olfactory bulb, where they differentiate as granular and periglomerular interneurons. The reported presence of differentiated neurons expressing the neuronal isoform of nitric oxide synthase (NOS) in the periphery of the neurogenic region and the organization of their varicose axons as a network in which the precursors are immersed raised the hypothesis that endogenous nitric oxide (NO) may participate in the control of neurogenesis in the subventricular zone. Systemic administration of the NOS inhibitors N -nitro-L-arginine methyl ester or 7-nitroindazole to adult mice produced a dose-and time-dependent increase in the number of mitotic cells in the subventricular zone, rostral migratory stream, and olfactory bulb, but not in the dentate gyrus of the hippocampus, without affecting apoptosis. In the subventricular zone, this effect was exerted selectively on a precursor subpopulation expressing nestin but not neuronal or glial cell-specific proteins. In addition, in the olfactory bulb, analysis of maturation markers in the newly generated neurons indicated that chronic NOS inhibition caused a delay in neuronal differentiation. Postmitotic cell survival and migration were not affected when NO production was impaired. Our results suggest that NO, produced by nitrergic neurons in the adult mouse subventricular zone and olfactory bulb, exerts a negative control on the size of the undifferentiated precursor pool and promotes neuronal differentiation.

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“…Neurogenesis in the dentate gyrus increases in response to external stimulation, suggesting a role in learning processes (27,28). A variety of insults to the brain induce the proliferation of immature neurons in both the SVZ and the subgranular layer (29)(30)(31). However, whether newly generated cells integrate into functional brain circuitry has remained unclear until recently (32,33).…”

mentioning

confidence: 99%

Robust in vivo gene transfer into adult mammalian neural stem cells by lentiviral vectors

Consiglio

Gritti

Dolcetta

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

159

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Stable genetic modification of adult stem cells is fundamental for both developmental studies and therapeutic purposes. Using in vivo marking studies, we showed that injection of lentiviral vectors (LVs) into the subventricular zone of the adult mouse brain enables efficient gene transfer into long-term self-renewing neural precursors and steady, robust vector expression in their neuronal progeny throughout the subventricular zone and its rostral extension, up to the olfactory bulb. By clonal and population analysis in culture, we proved that in vivo-marked neural precursors display self-renewal and multipotency, two essential characteristics of neural stem cells (NSCs). Thus, LVs efficiently target long-term repopulating adult NSCs, and the effect of the initial transduction is amplified by the continuous generation of NSC-derived, transduced progeny. LVs may thus allow novel studies on NSCs' physiology in vivo, and introduction of therapeutic genes into NSCs may allow the development of novel approaches for untreatable CNS diseases.

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Morphological bases for a role of nitric oxide in adult neurogenesis11Published on the World Wide Web on 25 May 2000.

Cited by 102 publications

References 33 publications

Nitric oxide negatively regulates mammalian adult neurogenesis

Nitric oxide negatively regulates mammalian adult neurogenesis

Nitric Oxide Is a Physiological Inhibitor of Neurogenesis in the Adult Mouse Subventricular Zone and Olfactory Bulb

Robust in vivo gene transfer into adult mammalian neural stem cells by lentiviral vectors

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