Signaling in adult neurogenesis: from stem cell niche to neuronal networks

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The mechanisms that determine why neurogenesis is restricted to few regions of the adult brain in mammals, in contrast to its more widespread nature in other vertebrates such as zebrafish, remain to be fully understood. The local environment must provide key signals that instruct stem cell and neurogenic fate, because non-neurogenic progenitors can be instructed towards neurogenesis in this environment. Here, we discuss the recent progress in understanding key factors in the local stem cell niche of the adult mammalian brain, including surprising sources of new signals such as endothelial cells, complement factors and microglia. Moreover, new insights have been gained into how neuronal diversity is instructed in adult neurogenesis, prompting a new view of stem and progenitor cell heterogeneity in the adult mammalian brain.

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)

  • B. Winner et al.

    Striatal deafferentation increases dopaminergic neurogenesis in the adult olfactory bulb

    Exp Neurol

    (2006)
  • F. Luzzati et al.

    Neurogenesis in the caudate nucleus of the adult rabbit

    J Neurosci

    (2006)
  • G.L. Ming et al.

    Adult neurogenesis in the mammalian central nervous system

    Annu Rev Neurosci

    (2005)
  • M.A. Curtis et al.

    Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension

    Science

    (2007)
  • A. Alvarez-Buylla et al.

    A unified hypothesis on the lineage of neural stem cells

    Nat Rev Neurosci

    (2001)
  • P. Chapouton et al.

    her5 expression reveals a pool of neural stem cells in the adult zebrafish midbrain

    Development

    (2006)
  • H. Grandel et al.

    Neural stem cells and neurogenesis in the adult zebrafish brain: origin, proliferation dynamics, migration and cell fate

    Dev Biol

    (2006)
  • E. Pellegrini et al.

    Identification of aromatase-positive radial glial cells as progenitor cells in the ventricular layer of the forebrain in zebrafish

    J Comp Neurol

    (2007)
  • F. Doetsch et al.

    Subventricular zone astrocytes are neural stem cells in the adult mammalian brain

    Cell

    (1999)
  • B. Seri et al.

    Astrocytes give rise to new neurons in the adult mammalian hippocampus

    J Neurosci

    (2001)
  • M.V. Sofroniew

    Reactive astrocytes in neural repair and protection

    Neuroscientist

    (2005)
  • R.M. Seaberg et al.

    Adult rodent neurogenic regions: the ventricular subependyma contains neural stem cells, but the dentate gyrus contains restricted progenitors

    J Neurosci

    (2002)
  • R. Seidenfaden et al.

    Glial conversion of SVZ-derived committed neuronal precursors after ectopic grafting into the adult brain

    Mol Cell Neurosci

    (2006)
  • L.S. Shihabuddin et al.

    Adult spinal cord stem cells generate neurons after transplantation in the adult dentate gyrus

    J Neurosci

    (2000)
  • F. Doetsch et al.

    Regeneration of a germinal layer in the adult mammalian brain

    Proc Natl Acad Sci USA

    (1999)
  • M.I. Givogri et al.

    Notch signaling in astrocytes and neuroblasts of the adult subventricular zone in health and after cortical injury

    Dev Neurosci

    (2006)
  • A. Androutsellis-Theotokis et al.

    Notch signalling regulates stem cell numbers in vitro and in vivo

    Nature

    (2006)
  • S. Ahn et al.

    In vivo analysis of quiescent adult neural stem cells responding to Sonic hedgehog

    Nature

    (2005)
  • M.A. Gates et al.

    Astrocytes and extracellular matrix following intracerebral transplantation of embryonic ventral mesencephalon or lateral ganglionic eminence

    Neuroscience

    (1996)
  • L.S. Campos et al.

    Notch, epidermal growth factor receptor, and beta1-integrin pathways are coordinated in neural stem cells

    J Biol Chem

    (2006)
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