Signaling in adult neurogenesis: from stem cell niche to neuronal networks
Introduction
With few exceptions [1], newborn neurons in the adult brains of mammals, including humans, are added only to the olfactory bulb and the granular layer of the dentate gyrus [2, 3, 4, 5]. By contrast, adult neurogenesis occurs in many brain regions in the adult zebrafish, and adult neural stem cells are harbored in strikingly discrete compartments [6•, 7•, 8•]. Notably, radial glia, which are a common source of neurons during development, are maintained into adulthood in the zebrafish brain. Indeed, radial glia themselves seem to be the neural stem and progenitor cells in the zebrafish adult brain [6•, 9], providing an exciting new model in which forward genetics could be used to better understand the maintenance of adult neural stem cells and neurogenesis.
In the adult mammalian brain, radial glia in the dentate gyrus and subset of astroglia [10] line the lateral wall of the lateral ventricle [5] also act as multipotent neural stem cells [11, 12, 13, 14] (but see [15]). These cells generate neurons and oligodendrocytes by a gradual lineage progression, becoming first intermediate fast proliferating precursors (transit-amplifying precursors) and then precursors that express neuronal traits (neuronal progenitors) (Figure 1; for review see [2]). Notably, however, many neuronal progenitors are not yet irreversibly committed to the neuronal lineage because they give rise to glia in an altered environment [16•]. Thus, the local environment in the neurogenic niche is required at various steps of lineage progression until the end of neuronal differentiation.
So which factors specify that radial glia in the dentate gyrus and the astroglia of the lateral ventricle function as stem cells, in pronounced contrast to astroglia in other areas of the adult mammalian brain? Transplantation experiments revealed the crucial role of the local environment — the stem cell niche — some while ago [17]. When dividing glial progenitors were isolated from the adult spinal cord and transplanted into the adult subependymal zone (SEZ), some of these were able to revert to neurogenesis, clearly demonstrating the powerful influence of the local niche. However, even within the zone of adult neurogenesis, not all astrocytes seem to act as stem cells. Astrocytes that express glial fibrillary acidic protein (GFAP), the glutamate transporter GLAST, S100β and glutamine synthetase are abundant in the stem cell niche (Figure 1b) but only some of these cells are slow proliferating and give rise to mature neurons in the olfactory bulb or the dentate gyrus [13, 14]. The other astrocytes might act as niche cells, possibly providing crucial signals to the diverse stem and progenitor cells in this lineage. However, upon injury and/or the depletion of the fast-proliferating transit-amplifying precursors and neuronal progenitors by AraC infusion, a higher number of astrocytes starts to divide [18, 19], suggesting that previously quiescent astrocytes in the adult SEZ can be recruited to become neural stem cells. Thus, an astrocyte in an appropriate environmental niche can become a neural stem cell in response to injury-derived signals. But which factors are responsible for this transition?
Section snippets
Niche signals to stem and progenitor cells
Interestingly, GFAP-positive glia in the SEZ express components of Notch signaling pathways, including the Notch1 receptor, Notch ligands and effectors (e.g. Hes and Hes-related proteins) [20], suggesting a possible role for Notch signaling in stem cell homeostasis (Box 1). Because Notch signaling implies cell–cell contact, it is an intriguing possibility hat contact of niche astrocytes with stem cell astrocytes is important. Indeed, Androutsellis-Theotokis et al. showed that the regulatory
Signals that direct and regulate migration of neuronal progenitors
Diffusible factors influence not only stem and progenitor cell fates but also the migration of neuronal progenitors along the rostral migratory stream (RMS). Gradients of chemorepulsive cues (decreasing rostrally) [36], chemoattractive cues (increasing rostrally) [37] and even signals from the ventricle [38, 39] drive and direct migrating neuronal progenitors rostrally. The transcription factor serum-responsive factor (SRF) might form an important link between these extracellular signals and
Control of the diversity of olfactory bulb interneurons
After arriving at the olfactory bulb, migrating neuronal progenitors switch from tangential chain migration to radial, single-cell migration. At this stage, they must know already whether to stop in the granule cell layer or to continue into the glomerular layer. Recent data suggest that this specification might occur at very early stages in the developmental lineage, possibly implying that there are novel sources of adult neural stem cells within the rostral migratory stream [31••].
Until
Survival at the final target
Regulation of neuronal survival by activity-mediated cues is crucial for neuronal network function. Many newly generated neurons actually die when they attempt to integrate into the functional network [54, 55]. PSA-NCAM-positive immature neurons express various subtypes of acetylcholine receptor that might mediate the increase in neuronal survival that is seen in both the dentate gyrus and the olfactory bulb upon stimulation of the direct cholinergic innervation into these regions [56]. These
Conclusions
Taken together, recent results indicate that extrinsic signals are crucial regulators throughout adult neurogenesis: they regulate neural stem cell and progenitor cell fate; they determine which neuronal subtypes migrate from the local stem cell niche along the rostral migratory stream into the olfactory bulb; and the local environment in the olfactory bulb itself determines the outcome of adult neurogenesis by regulating the types and numbers of neurons that integrate and survive.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
References (61)
- et al.
Evidence of newly generated neurons in the human olfactory bulb
Brain Res Dev Brain Res
(2004) - et al.
Conserved and acquired features of adult neurogenesis in the zebrafish telencephalon
Dev Biol
(2006) - et al.
PDGFR alpha-positive B cells are neural stem cells in the adult SVZ that form glioma-like growths in response to increased PDGF signaling
Neuron
(2006) - et al.
Inducible gene deletion in astroglia and radial glia — a valuable tool for functional and lineage analysis
Glia
(2006) - et al.
Neuronal replacement from endogenous precursors in the adult brain after stroke
Nat Med
(2002) - et al.
Retinoic acid is required early during adult neurogenesis in the dentate gyrus
Proc Natl Acad Sci USA
(2006) - et al.
Pigment epithelium-derived factor is a niche signal for neural stem cell renewal
Nat Neurosci
(2006) - et al.
The zinc finger transcription factor Sp8 regulates the generation and diversity of olfactory bulb interneurons
Neuron
(2006) - et al.
Generation of GABAergic and dopaminergic interneurons from endogenous embryonic olfactory bulb precursor cells
Development
(2006) - et al.
Impairment of radial-arm maze performance in rats following lesions involving the cholinergic medial pathway: reversal by arecoline and differential effects of muscarinic and nicotinic antagonists
Neuroscience
(1991)
Striatal deafferentation increases dopaminergic neurogenesis in the adult olfactory bulb
Exp Neurol
Neurogenesis in the caudate nucleus of the adult rabbit
J Neurosci
Adult neurogenesis in the mammalian central nervous system
Annu Rev Neurosci
Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension
Science
A unified hypothesis on the lineage of neural stem cells
Nat Rev Neurosci
her5 expression reveals a pool of neural stem cells in the adult zebrafish midbrain
Development
Neural stem cells and neurogenesis in the adult zebrafish brain: origin, proliferation dynamics, migration and cell fate
Dev Biol
Identification of aromatase-positive radial glial cells as progenitor cells in the ventricular layer of the forebrain in zebrafish
J Comp Neurol
Subventricular zone astrocytes are neural stem cells in the adult mammalian brain
Cell
Astrocytes give rise to new neurons in the adult mammalian hippocampus
J Neurosci
Reactive astrocytes in neural repair and protection
Neuroscientist
Adult rodent neurogenic regions: the ventricular subependyma contains neural stem cells, but the dentate gyrus contains restricted progenitors
J Neurosci
Glial conversion of SVZ-derived committed neuronal precursors after ectopic grafting into the adult brain
Mol Cell Neurosci
Adult spinal cord stem cells generate neurons after transplantation in the adult dentate gyrus
J Neurosci
Regeneration of a germinal layer in the adult mammalian brain
Proc Natl Acad Sci USA
Notch signaling in astrocytes and neuroblasts of the adult subventricular zone in health and after cortical injury
Dev Neurosci
Notch signalling regulates stem cell numbers in vitro and in vivo
Nature
In vivo analysis of quiescent adult neural stem cells responding to Sonic hedgehog
Nature
Astrocytes and extracellular matrix following intracerebral transplantation of embryonic ventral mesencephalon or lateral ganglionic eminence
Neuroscience
Notch, epidermal growth factor receptor, and beta1-integrin pathways are coordinated in neural stem cells
J Biol Chem
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