Biochimica et Biophysica Acta (BBA) - General Subjects
ReviewSignaling mechanisms regulating adult neural stem cells and neurogenesis☆
Highlights
► Adult neurogenesis is regulated via both extrinsic environmental influences and intrinsic genetic factors. ► We review individual signaling mechanisms and their cross-talk in regulating adult neurogenesis. ► We highlight emerging principles in the growing field of adult neural stem cell biology.
Introduction
Neural stem cells (NSCs) are characterized by the capacity to continuously self-renew and generate a multitude of neuronal and glial lineages [1], [2]. Neurogenesis in the mammalian brain involves multiple, complex processes that include proliferation, fate specification, differentiation, maturation, migration, and functional integration of newborn cells into the existing neuronal circuitry [1]. Following the discovery that neurogenesis persists throughout life in the adult mammalian brain, including in humans [3], [4], [5], recent studies have linked variable levels of adult neurogenesis to brain function in the normal and diseased brain. These findings, coupled with the possibility of using NSCs in treatment of neurodegenerative disease and psychiatric disorders, have generated new interest in understanding the molecular mechanisms underlying adult neurogenesis.
Active neurogenesis occurs primarily in two regions of the adult mammalian brain: the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus (DG) (Fig. 1) [6], [7]. Quiescent or slowly dividing ependymal and subependymal cells expressing GFAP- and Prominin-1/CD133 are thought to be the primary NSCs in the adult SVZ (type B cells) [6], [8], although Prominin-1/CD133 is expressed by other non-CNS stem cells as well, such as myogenic and hematopoietic stem cells [9]. These GFAP- and Prominin-1/CD133-expressing cells with stem cell properties reside in the wall of the lateral ventricle and give rise to transit amplifying cells (type C cells) via asymmetric division. Transit amplifying cells, which express the receptor for epidermal growth factor [10], [11], give rise to polysialylated neural adhesion molecule (PSA-NCAM)-expressing neuroblasts (type A cells) that migrate into the olfactory bulb via the rostral migratory stream (RMS) and differentiate into GABA- and dopamine-producing granule and periglomerular interneurons [6], [12], [13]. In the adult hippocampus, the SGZ of the DG contains GFAP-, Nestin-, and Sox2-expressing radial glia-like cells (RGLs) that act as quiescent NSCs. Recent clonal analysis of individual RGLs has revealed both self-renewal and multipotential capacities in this population that can generate additional RGLs, neurons and astroyctes [14]. Asymmetric division of RGLs can give rise to neuronal lineage restricted progenitor daughter cells (type 2 cell) that express Nestin and Sox2, but not GFAP [15]. Type 2 cells in turn give rise to neuroblasts expressing doublecortin (DCX) and PSA-NCAM which then differentiate into glutamatergic dentate granule cells [16], [17].
Neurogenesis in adults is dynamically regulated by a number of intrinsic as well as extrinsic factors [18]. Endogenous extrinsic factors in the local microenvironment, often referred to as the “neurogenic niche” or “stem cell niche”, include neural precursor cells, surrounding mature cells, cell-to-cell interactions, cilia, secreted factors, and neurotransmitters [6], [19]. Microenvironments of the SVZ and SGZ, but not other brain regions, are thought to have specific factors that are permissive for the differentiation and integration of new neurons, as evidenced by a pivotal study showing that adult hippocampal astrocytes promote neuronal differentiation of adult-derived hippocampal progenitor cells in vitro [20].
The importance of the stem cell niche in determining the fate of adult NSCs is highlighted by several different transplantation experiments. SVZ-derived committed neural precursor cells differentiate into glia cells when grafted into ectopic non-neurogenic regions of the brain [21]. Furthermore, SVZ precursor cells generate hippocampal neurons when transplanted into the DG of the hippocampus, whereas SGZ precursors generate olfactory interneurons after transplantation into the RMS [22]. Similarly, neural precursor cells derived from the adult spinal cord differentiate into granule cell neurons after implantation into the hippocampus, but fail to generate neuronal phenotypes and differentiate into glial cells after transplantation back to their original site in the spinal cord [23]. In contrast, Merkle et al. showed that SVZ-derived NSCs maintained their region-specific potential in vivo, and that environmental factors at the host graft site were not sufficient to respecify the grafted cells after heterotopic transplantation [24].
Recently developed tools allowing inducible alteration of gene expression specifically within adult NSCs have provided new insights in the mechanisms regulating neurogenesis in vivo. Viral-mediated gene transfer in vivo utilizes retro- or lentiviruses and allows long-lasting genetic manipulation at the site of virus infusion and transgenic mouse lines enable inducible and cell-specific knock-out, knockdown, or overexpression of a specific gene of interest. With these and other techniques, several soluble and membrane-bound extracellular factors and their intracellular signaling cascades have recently been identified as determinants of the local microenvironment of the SVZ and SGZ, including Wnt, sonic hedgehog, Notch, BMPs, neurotrophins, and neurotransmitters. Furthermore, cell-intrinsic mechanisms including transcription factors and epigenetic regulators of neurogenesis have recently been shown to be crucially involved in modulating neurogenesis in the adult brain. In this review, we summarize the role of both external and cell-intrinsic signals in regulating adult neurogenesis. Furthermore, we discuss key signaling pathways regulating different stages of adult neurogenesis, including neural stem cell proliferation and lineage differentiation, and migration and integration of the developing neuron in the adult brain (Table 1, Fig. 1).
Section snippets
Wnt/beta-catenin pathway
The Wnt signaling pathway is a highly conserved signaling pathway that has been implicated in nervous system development, including neural tube formation, dorsal root ganglia development, and midbrain development [25], [26], [27]. Disruption of the physiological Wnt–signaling pathway has been associated with several CNS pathologies, including schizophrenia, mood disorders, autism, and Alzheimer's disease [28], [29], [30], [31].
Wnt ligands constitute a family of auto- and paracrine secreted
Notch pathway
Notch signaling impinges on a wide array of cellular processes in the developing nervous system, including cell proliferation, differentiation, and apoptosis [45], [46], [47]. Notch receptors are single-pass transmembrane heterodimers that are activated upon forming a binding complex with their membrane-bound ligands on the neighboring cell, Delta and Jagged. Ligand binding results in gamma-secretase mediated cleavage of the transmembrane domain, and subsequent release of the notch
Sonic hedgehog pathway
Sonic hedgehog (Shh) is a soluble extracellular signaling protein that was first discovered to have a role in cell differentiation in the neural tube and limb bud [61]. Shh signaling has since been found to be crucial in regulating various processes during development of the nervous system, such as ventral forebrain neuronal differentiation, midbrain dopaminergic differentiation, and cerebellar neuronal precursor proliferation [62], [63], [64]. Shh mediates its action via a receptor complex
Growth factors and neurotrophic factors
Neurotrophic factors are extracellular signaling proteins that play important roles in both the developing and adult central nervous system [78], [79], [80]. In mammals, four neurotrophic factors have been identified, namely nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4/5 (NT-4/5) [81], [82]. Neurotrophins bind to receptor tyrosine kinases known as Trk receptors and their co-receptor p75NTR. There are three different Trk
Bone morphogenetic proteins
Bone morphogenetic proteins (BMPs) comprise a group of multifunctional extracellular signaling molecules of which over 20 members have been identified to date, and constitute the largest subgroup of the transforming growth factor-beta (TGF-beta) superfamily [123]. BMPs are highly expressed in the embryonic and adult nervous system and play pivotal roles in regulating a wide variety of cellular processes, including cell survival, proliferation and fate specification [124], [125]. Activities of
Neurotransmitters
Neurotransmitters are small diffusible molecules that serve as the basis of chemical communication between neurons [138], [139], [140]. Accumulating evidence also suggests essential roles of neurotransmitters in regulating adult neural progenitor cell proliferation, differentiation, and synaptic integration, as well as activity-dependent adult neurogenesis. Glutamate is an excitatory neurotransmitter that utilizes several different receptor subtypes, namely ionotropic NMDA, AMPA and kainic acid
Transcription factors
cAMP response element-binding protein (CREB) is a transcription factor that is a central regulator of cellular growth and development, and common final phosphorylation substrate for several kinase-mediated signaling pathways, including the cAMP/Protein kinase A pathway, calcium–calmodulin mediated NMDA receptor signaling, as well as MAP kinase signaling induced by neurotrophins via Trk receptors [168], [169], [170], [171]. Upon phosphorylation, CREB dimerizes and binds to cAMP response elements
Epigenetic regulators
Epigenetic mechanisms, including DNA methylation and histone modification, have recently emerged as an important link between external environmental influences and transcriptional control of gene expression in NSCs [216]. Epigenetic modification implies heritable changes in patterns of gene expression that are not encoded in the primary DNA sequence itself, thus resulting in new cellular phenotypes without altering the actual genomic sequence [217]. DNA methylation predominantly occurs at the
Conclusion
The recent discovery of ongoing neurogenesis in the adult mammalian brain has demonstrated a novel capacity of the mature nervous system to support the integration of de novo populations of neurons. While we are just beginning to understand mechanisms and regulators involved in adult neurogenesis, several common principles have emerged over the last decade. Adult neurogenesis recapitulates many features of embryonic neurogenesis, and several intrinsic and extracellular factors, such as trophic
Acknowledgements
We thank K. Christian for comments. The research in Dr. Song's laboratory was supported by NIH (NS047344 and MH087874), IMHRO, and SAFRI. R. Faigle is the recipient of an NIH/National Institute of Neurological Disorders and Stroke R25 training grant.
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This article is part of a Special Issue entitled Biochemistry of Stem Cells.