Trends in Neurosciences
Volume 37, Issue 10, October 2014, Pages 563-571
Journal home page for Trends in Neurosciences

Feature Review
Special Issue: Circuit Development and Remodeling
Adult neural stem cells stake their ground

https://doi.org/10.1016/j.tins.2014.08.006Get rights and content

Highlights

  • Neural stem cells retain regional identity into adulthood.

  • Cerebrospinal fluid, vasculature, and neuronal activity control adult V-SVZ neurogenesis.

  • New roles for chromatin modifiers and non-coding RNAs are discovered in the V-SVZ.

The birth of new neurons in the walls of the adult brain lateral ventricles has captured the attention of many neuroscientists for over 2 decades, yielding key insights into the identity and regulation of neural stem cells (NSCs). In the adult ventricular–subventricular zone (V–SVZ), NSCs are a specialized form of astrocyte that generates several types of neurons for the olfactory bulb. In this review, we discuss recent findings regarding the unique organization of the V–SVZ NSC niche, the multiple regulatory controls of neuronal production, the distinct regional identities of adult NSCs, and the epigenetic mechanisms that maintain adult neurogenesis. Understanding how V–SVZ NSCs establish and maintain lifelong neurogenesis continues to provide surprising insights into the cellular and molecular regulation of neural development.

Section snippets

Type B1 cells: a ‘displaced’ form of radial glia?

Consistent with their astrocytic morphology and ultrastructure, B1 cells express glial markers such as the glial-fibrillary acidic protein (GFAP), glutamate aspartate transporter (GLAST), and brain lipid binding protein (BLBP). Recent work indicates that B1 cells can exist in either a quiescent or activated state 10, 11. Interestingly, quiescent B1 cells do not appear to express Nestin, an intermediate filament protein that has long been considered to be a marker of NSCs. By contrast, activated

The regional identity of V–SVZ NSCs

NSCs located in geographically distinct regions of the ventricle walls produce different types of OB neurons 21, 22 (Figure 2). For instance, dorsal NSCs produce superficial granule cells (GCs) and anteriorly TH-positive periglomerular cells (PGCs), but few, if any, calbindin-positive PGCs. By contrast, ventral NSCs produce deep GCs and calbindin-positive, but not tyrosine hydroxylase (TH)-positive, periglomerular cells. Results from heterotopic grafting of NSCs (e.g., ventral NSCs transplanted

Activating the stem cell niche with blood vessels, ependyma, and neurons

Stem cells reside in a specialized microenvironment – or ‘niche’ – that contributes to the regulation of proliferation and progenitor cell differentiation. Similar to other stem cell populations 28, 29, 30, NSCs of the V–SVZ are regulated by a multitude of niche signaling pathways including SHH, Wnt, Notch, BMPs, and ephrins (see 4, 31 for more extensive review). The local vascular plexus also appears to be a source of important extrinsic signals for the regulation of V–SVZ progenitor cells.

Cell intrinsic signals for long-term and complex patterns in neurogenesis

SOX2 is a sequence-specific DNA binding transcription factor with many critical functions in a wide variety of cell populations throughout development [52]. How SOX2 performs such diverse roles in different cell types is not well understood, and recent studies of the V–SVZ lineage have shed light on this important and complex issue (Figure 3A). In the V–SVZ, SOX2 is expressed in essentially all V–SVZ cell types, including B1 cells [53]. B1 cells express the PRX1 homeobox transcription factor,

Epigenetic mechanisms for the maintenance of neurogenic competence

It has been suggested that B1 cells, like other stem cell populations, can self-renew and have the ability to generate multiple cell types. Conceptually, this cellular state of ‘stemness’ involves the expression of certain genes, repression of other specific loci, and transcriptional plasticity of genes necessary for lineage specification. Such complex patterns of transcriptional regulation involve the structure and function of chromatin. Chromatin states are regulated by both non-covalent and

The human brain V–SVZ

Recent studies have revealed intriguing differences between the rodent and human V–SVZ. In young children, the V–SVZ contains many DCX-positive cells, and there is a prominent RMS to the OB [95]. Furthermore, the brain of infants also has a medial migratory stream of young neurons from the V–SVZ to the medial prefrontal cortex, which is a migratory path not evident in the rodent brain. After 18 months of age, few DCX-positive cells are observed in the human V–SVZ. Instead, there is a prominent

Concluding remarks

Over the past 2 decades, in vivo and in vitro studies of the V–SVZ have revealed the experimental advantages of studying a germinal niche that remains active throughout adult life. As discussed above, neurogenesis in the V–SVZ involves an intriguing interplay between niche signals including epithelial and vascular-derived signals, as well as activity-dependent neurotransmitters. Furthermore, the maintenance of long-term neurogenesis and regional NSC specification has been discovered to involve

Acknowledgments

This work was supported by NIH grant DP2-OD006505, VA grant 1I01 BX000252, a Sontag Foundation Award, and a generous gift from the Shurl and Kay Curci Foundation to D.A.L. A.A.B is the Heather and Melanie Muss Endowed Chair and is supported by NIH grants HD032116, NS28478, and a generous gift from the J.G. Bowes Foundation. We thank Joseph Elsbernd and Luis Fuentealba for their helpful edits and comments on the manuscript and Ken Probst for illustrations.

Glossary

Regional identity
the developmental specialization of precursor cells based on their physical location.
Epigenetics
the study of heritable patterns of gene expression that do not involve changes to the DNA sequence.
Chromatin
the dynamic polymer of DNA and histone proteins. The nucleosome – approximately 146 bp of DNA wrapped approximately twice around an octamer of the four core histone proteins (H2A, H2B, H3, H4) – is the basic subunit of chromatin. Chromatin can undergo non-covalent and covalent

References (100)

  • M. Tavazoie

    A specialized vascular niche for adult neural stem cells

    Cell Stem Cell

    (2008)
  • E. Kokovay

    Adult SVZ lineage cells home to and leave the vascular niche via differential responses to SDF1/CXCR4 signaling

    Cell Stem Cell

    (2010)
  • P. Paez-Gonzalez

    Ank3-dependent SVZ niche assembly is required for the continued production of new neurons

    Neuron

    (2011)
  • D.A. Lim

    Noggin antagonizes BMP signaling to create a niche for adult neurogenesis

    Neuron

    (2000)
  • J.M. Brezun et al.

    Depletion in serotonin decreases neurogenesis in the dentate gyrus and the subventricular zone of adult rats

    Neuroscience

    (1999)
  • C.K. Tong

    Axonal control of the adult neural stem cell niche

    Cell Stem Cell

    (2014)
  • J. Alfonso

    Diazepam binding inhibitor promotes progenitor proliferation in the postnatal SVZ by reducing GABA signaling

    Cell Stem Cell

    (2012)
  • A. Sarkar et al.

    The sox family of transcription factors: versatile regulators of stem and progenitor cell fate

    Cell Stem Cell

    (2013)
  • K. Shimozaki

    SRY-box-containing gene 2 regulation of nuclear receptor tailless (Tlx) transcription in adult neural stem cells

    J. Biol. Chem.

    (2012)
  • R.R. Waclaw

    The zinc finger transcription factor Sp8 regulates the generation and diversity of olfactory bulb interneurons

    Neuron

    (2006)
  • T. Kouzarides

    Chromatin modifications and their function

    Cell

    (2007)
  • J. Ninkovic

    The BAF complex interacts with Pax6 in adult neural progenitors to establish a neurogenic cross-regulatory transcriptional network

    Cell Stem Cell

    (2013)
  • S.B. Foti

    HDAC inhibitors dysregulate neural stem cell activity in the postnatal mouse brain

    Int. J. Dev. Neurosci.

    (2013)
  • S. He

    Bmi-1 over-expression in neural stem/progenitor cells increases proliferation and neurogenesis in culture but has little effect on these functions in vivo

    Dev. Biol.

    (2009)
  • S. Bertani

    The noncoding RNA Mistral activates Hoxa6 and Hoxa7 expression and stem cell differentiation by recruiting MLL1 to chromatin

    Mol. Cell

    (2011)
  • A.D. Ramos

    Integration of genome-wide approaches identifies lncRNAs of adult neural stem cells and their progeny in vivo

    Cell Stem Cell

    (2013)
  • A. Ernst

    Neurogenesis in the striatum of the adult human brain

    Cell

    (2014)
  • J. Altman

    Autoradiographic and histological studies of postnatal neurogenesis. 3. Dating the time of production and onset of differentiation of cerebellar microneurons in rats

    J. Comp. Neurol.

    (1969)
  • S.A. Goldman et al.

    Neuronal production, migration, and differentiation in a vocal control nucleus of the adult female canary brain

    Proc. Natl. Acad. Sci. U.S.A.

    (1983)
  • M. Sakamoto

    Continuous postnatal neurogenesis contributes to formation of the olfactory bulb neural circuits and flexible olfactory associative learning

    J. Neurosci.

    (2014)
  • G. Lepousez

    The impact of adult neurogenesis on olfactory bulb circuits and computations

    Annu. Rev. Physiol.

    (2013)
  • N. Heins

    Glial cells generate neurons: the role of the transcription factor Pax6

    Nat. Neurosci.

    (2002)
  • A. Kriegstein et al.

    The glial nature of embryonic and adult neural stem cells

    Annu. Rev. Neurosci.

    (2009)
  • J.K. Mich

    Prospective identification of functionally distinct stem cells and neurosphere-initiating cells in adult mouse forebrain

    Elife

    (2014)
  • G. Ponti

    Cell cycle and lineage progression of neural progenitors in the ventricular-subventricular zones of adult mice

    Proc. Natl. Acad. Sci. U.S.A.

    (2013)
  • F. Doetsch et al.

    Network of tangential pathways for neuronal migration in adult mammalian brain

    Proc. Natl. Acad. Sci. U.S.A.

    (1996)
  • F.T. Merkle

    Radial glia give rise to adult neural stem cells in the subventricular zone

    Proc. Natl. Acad. Sci. U.S.A.

    (2004)
  • J.C. Conover

    Disruption of Eph/ephrin signaling affects migration and proliferation in the adult subventricular zone

    Nat. Neurosci.

    (2000)
  • X. Huang

    Transventricular delivery of Sonic hedgehog is essential to cerebellar ventricular zone development

    Proc. Natl. Acad. Sci. U.S.A.

    (2010)
  • F.T. Merkle

    Mosaic organization of neural stem cells in the adult brain

    Science

    (2007)
  • A. Alvarez-Buylla

    The heterogeneity of adult neural stem cells and the emerging complexity of their niche

    Cold Spring Harb. Symp. Quant. Biol.

    (2008)
  • M. Kohwi

    A subpopulation of olfactory bulb GABAergic interneurons is derived from Emx1- and Dlx5/6-expressing progenitors

    J. Neurosci.

    (2007)
  • R.E. Ventura et al.

    Dorsal radial glia generate olfactory bulb interneurons in the postnatal murine brain

    J. Neurosci.

    (2007)
  • M. Alonso

    Turning astrocytes from the rostral migratory stream into neurons: a role for the olfactory sensory organ

    J. Neurosci.

    (2008)
  • E. Vergano-Vera

    Generation of GABAergic and dopaminergic interneurons from endogenous embryonic olfactory bulb precursor cells

    Development

    (2006)
  • F.T. Merkle

    Adult neural stem cells in distinct microdomains generate previously unknown interneuron types

    Nat. Neurosci.

    (2014)
  • R. Schofield

    The relationship between the spleen colony-forming cell and the haemopoietic stem cell

    Blood Cells

    (1978)
  • F.M. Watt et al.

    Out of Eden: stem cells and their niches

    Science

    (2000)
  • L. Katsimpardi

    Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors

    Science

    (2014)
  • Q. Shen

    Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells

    Science

    (2004)
  • Cited by (139)

    • Synaptogenesis in the adult CNS-olfactory system

      2020, Synapse Development and Maturation: Comprehensive Developmental Neuroscience
    View all citing articles on Scopus
    View full text