Signaling in adult neurogenesis

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Neural stem cells (NSCs) in the adult brain continuously supply new neurons to the hippocampal dentate gyrus (DG) and the olfactory bulb (OB). Recent studies indicate that the progression from neural precursor cells (NPCs) to mature neurons is tightly controlled by coordinate cell-intrinsic programs and external signals within the neurogenic niche. In this review, we summarize both classes of regulatory factors involved in distinct stages of adult neurogenesis, including proliferation and lineage differentiation of NSCs, migration of neuroblasts and integration of newborn neurons. A full understanding of the wide variety of signaling pathways will ultimately provide precise targets for therapeutic applications.

Introduction

Over the last two decades, it has become apparent that persistent neurogenesis throughout life occurs in two specific brain areas of adult mammals: the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus (DG) (Figure 1a) [1, 2, 3, 4]. The newborn neuronal cells originate from adult neural stem cells (NSCs) in the germinal zones, which are defined by their ability to self-replicate and differentiate into multiple neural lineages, including neurons, astrocytes, and oligodendrocytes [5]. Two types of NSCs have been identified based on their morphology, proliferative behavior, and marker expression, although their origin and identity remain to be defined (Figure 1b and c) [6, 7, 8]. In the SVZ, slowly dividing, radial glia-like progenitors (type B cells) that express GFAP and CD133 have been hypothesized to be the primary NSCs in vivo. They are hypothesized to generate rapidly dividing, transit-amplifying progenitors (type C cells) that typically have either no or a very short process and are characterized as positive for Dlx2, Mash1, and EGFR. The majority of these intermediate progenitors subsequently give rise to DCX+ PSA-NCAM+ neuroblasts (type A cells) that migrate into the olfactory bulb (OB) through the rostral migratory stream (RMS) and differentiate into GABA-producing and dopamine-producing interneurons. In parallel, a population of GFAP+ Sox2+ Nestin+ radial cells (type 1 cells) is found to act as quiescent NSCs in the SGZ. They may generate actively self-renewing nonradial progenitors (type 2 cells) expressing Sox2 and Nestin but not GFAP, and type 2 cells in turn give rise to DCX+ neuroblasts that predominantly differentiate into local glutamatergic dentate granule cells (DGCs). It was recently found that a subset of type 2 Sox2+ cells has the potential to self-renew and generate both neurons and astrocytes, indicating a possible reciprocal lineage relationship between type 1 and type 2 cells in the SGZ [9].

Although NSCs have been derived from a variety of adult brain areas, active neurogenesis seems to be restricted to SVZ and SGZ under physiological conditions in vivo. Committed neural precursor cells (NPCs) from SVZ differentiate into glia when grafted outside their normal neurogenic environment [10], whereas glial progenitors derived from spinal cord generate neurons when transplanted into the DG [11]. Furthermore, adult hippocampal NPCs grafted into RMS differentiate appropriately into neurons of nonhippocampus phenotype, whereas those grafted into non-neurogenic sites showed no neuronal differentiation [12]. These transplantation experiments clearly demonstrate that the microenvironment or neurogenic niche plays a crucial role in determining where and how neurogenesis can occur. However, it is also important to recognize that, even within the germinal zones of the adult brain, only a subset of marker-expressing cells are capable of generating neurons. Besides, the populations of adult NSCs are inherently diverse in their nature, as evidenced by the fact that NSCs from different regions of SVZ produce different neuronal subtypes, even when heterotopically grafted or grown in culture [13]. Thus, the progression from NSCs to mature neurons is subject to a tightly coordinated control by a multitude of cell-intrinsic and extracellular factors. Here we review recent progress in our understanding of the molecular mechanisms regulating the developmental steps of neurogenesis in the adult hippocampus and forebrain, including proliferation and fate specification of NPCs, their subsequent migration, and functional maturation.

Section snippets

Signals directing proliferation and fate commitment of NSCs

The extracellular signaling mechanisms that are present in the microenvironments of the SVZ and SGZ provide them with the unique ability to support and promote neurogenesis (Table 1). Signaling molecules that are critical during embryonic development of the nervous system are conserved and continue to modulate NSC activity and adult neurogenesis. The Wnt signaling pathway influences NSC proliferation and differentiation during embryonic development. Recent studies have also identified the Wnt

Neuroblast migration from the SVZ to the OB

Neuroblasts generated in the SVZ migrate along the RMS by chain migration to the OB [41], where they differentiate into GABAergic neurons that integrate into the pre-existing circuits of the granule cell layer and contribute to olfactory learning [42]. The proper migration of the neuroblast from the germinal zone to their target destination underlies the ability of the newborn neurons to populate the OB. Recent studies have identified Shh as playing a crucial role in neuroblast migration along

Regulation of neuronal integration in the adult brain

A large portion of newborn neurons dies within four weeks after birth. Their survival is subject to regulation by diverse mechanisms, and so is their morphological/physiological development before integration into the existing neural circuitry (Figure 2). Neuroblasts born in the postnatal SVZ express NMDA receptors (NMDARs) during migration to the OB. The NMDAR activity is regulated by glutamate released from astrocyte-like cells that ensheathe the neuroblasts. Single-cell NMDAR knockout leads

Conclusions

These recent studies highlight the broad range of signaling mechanisms involved in the regulation of adult neurogenesis. A number of signaling pathways, such as Wnt and Shh, are conserved and function prominently in both the developing nervous system and the germinal zones of the adult brain, supporting the neurogenic niche. Additionally, intrinsic factors such as miRNAs and transcription factors are increasingly demonstrating the cell-autonomous characteristics that provide the NSCs and NPCs

References and recommended reading

Papers of particular interest, published within the period of the review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank M.L. Gage for editorial comments and J. Simon for illustrations. This work is funded by the National Institute of Mental Health (MH-090258), the James S. McDonnell Foundation, and Glenn Center for Aging Research fellowship (S.W. Lee).

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