Signaling in adult neurogenesis
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).
References (72)
- et al.
For the long run: maintaining germinal niches in the adult brain
Neuron
(2004) - et al.
Glial influences on neural stem cell development: cellular niches for adult neurogenesis
Curr Opin Neurobiol
(2005) - et al.
Mechanisms and functional implications of adult neurogenesis
Cell
(2008) - et al.
In vivo fate analysis reveals the multipotent and self-renewal capacities of Sox2+ neural stem cells in the adult hippocampus
Cell Stem Cell
(2007) - et al.
Adult spinal cord stem cells generate neurons after transplantation in the adult dentate gyrus
J Neurosci
(2000) - et al.
In vivo analysis of Ascl1 defined progenitors reveals distinct developmental dynamics during adult neurogenesis and gliogenesis
J Neurosci
(2007) - et al.
Adult generation of glutamatergic olfactory bulb interneurons
Nat Neurosci
(2009) - et al.
Adult-born and preexisting olfactory granule neurons undergo distinct experience-dependent modifications of their olfactory responses in vivo
J Neurosci
(2005) - et al.
GABAergic signaling to newborn neurons in dentate gyrus
J Neurophysiol
(2005) - et al.
Variant brain-derived neurotrophic factor (Val66Met) alters adult olfactory bulb neurogenesis and spontaneous olfactory discrimination
J Neurosci
(2008)
Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain
Cell
A functional role for adult hippocampal neurogenesis in spatial pattern separation
Science
Neurogenesis in the adult human hippocampus
Nat Med
Continuation of neurogenesis in the hippocampus of the adult macaque monkey
Proc Natl Acad Sci U S A
Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation
J Neurosci
Long-distance neuronal migration in the adult mammalian brain
Science
Mammalian neural stem cells
Science
Glial conversion of SVZ-derived committed neuronal precursors after ectopic grafting into the adult brain
Mol Cell Neurosci
Differentiation of adult hippocampus-derived progenitors into olfactory neurons in vivo
Nature
Mosaic organization of neural stem cells in the adult brain
Science
Wnt signalling regulates adult hippocampal neurogenesis
Nature
Endogenous Wnt signaling maintains neural progenitor cell potency
Stem Cells
Wnt-mediated activation of NeuroD1 and retro-elements during adult neurogenesis
Nat Neurosci
Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo
Nat Neurosci
Hedgehog signaling and primary cilia are required for the formation of adult neural stem cells
Nat Neurosci
The nuclear receptor tailless is required for neurogenesis in the adult subventricular zone
Genes Dev
Expression and function of orphan nuclear receptor TLX in adult neural stem cells
Nature
A role for adult TLX-positive neural stem cells in learning and behaviour
Nature
Orphan nuclear receptor TLX recruits histone deacetylases to repress transcription and regulate neural stem cell proliferation
Proc Natl Acad Sci U S A
Orphan nuclear receptor TLX activates Wnt/beta-catenin signalling to stimulate neural stem cell proliferation and self-renewal
Nat Cell Biol
Impaired generation of mature neurons by neural stem cells from hypomorphic Sox2 mutants
Development
Sox2 deficiency causes neurodegeneration and impaired neurogenesis in the adult mouse brain
Development
MicroRNAs: target recognition and regulatory functions
Cell
Identification of tissue-specific microRNAs from mouse
Curr Biol
miR-124 regulates adult neurogenesis in the subventricular zone stem cell niche
Nat Neurosci
A functional study of miR-124 in the developing neural tube
Genes Dev
Cited by (174)
Hesperidin ameliorates impairment in hippocampal neural stem cells related to apoptosis induced by methotrexate in adult rats
2023, Biomedicine and PharmacotherapyGPR37 modulates progenitor cell dynamics in a mouse model of ischemic stroke
2021, Experimental NeurologyTypes of biomaterials useful in brain repair
2021, Neurochemistry InternationalTwo-photon live imaging of direct glia-to-neuron conversion in the mouse cortex
2024, Neural Regeneration ResearchIron overload suppresses hippocampal neurogenesis in adult mice: Implication for iron dysregulation-linked neurological diseases
2024, CNS Neuroscience and Therapeutics
- *
These authors contributed equally to this work.