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Neural stem cells in mammalian development
Florian T Merkle and Arturo Alvarez-Buylla
Neural stem cells (NSCs) are primary progenitors that give rise
to neurons and glia in the embryonic, neonatal and adult brain.
In recent years, we have learned three important things about
these cells. First, NSCs correspond to cells previously thought
to be committed glial cells. Second, embryonic and adult NSCs
are lineally related: they transform from neuroepithelial cells
into radial glia, then into cells with astroglial characteristics.
Third, NSCs divide asymmetrically and often amplify the
number of progeny they generate via symmetrically dividing
intermediate progenitors. These advances challenge our
traditional perceptions of glia and stem cells, and provide the
foundation for understanding the molecular basis of
mammalian NSC behavior.
Addresses
Department of Neurological Surgery and Program in Developmental and
Stem Cell Biology, University of California, San Francisco, Box 0525,
HSW 1201A, San Francisco, California 94143 USA
Corresponding author: Alvarez-Buylla, Arturo
(abuylla@stemcell.ucsf.edu)
Current Opinion in Cell Biology 2006, 18:1–6
This review comes from a themed issue on
Cell differentiation
Edited by Marianne Bronner-Fraser
0955-0674/$ – see front matter
# 2006 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.ceb.2006.09.008
Introduction
The central nervous system (CNS) develops from a small
number of highly plastic cells that proliferate, acquire
regional identities and produce different cell types.
These cells have been defined as neural stem cells
(NSCs) on the basis of their potential to generate multiple
cell types (e.g. neurons and glia) and their ability to selfrenew in vitro. However, this definition does not necessarily reflect the behavior of these cells in vivo. In the
brain, it appears that NSCs are specified in space and time
(see section below on ‘The developing NSC’), becoming
spatially heterogeneous and generating a progressively
restricted repertoire of cell types. It is also not clear how
strictly NSCs self-renew in vivo, since their potential
progressively changes and they generate different progeny over the course of development. In this review we
will define a NSC, or primary progenitor, as a neural cell
that maintains the potential to generate multiple cell
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types over long periods of time. NSCs from the same
region that maintain these characteristics but change in
appearance and/or potential over time are said to belong
to the same lineage.
The lineage of mammalian NSCs lining the lateral ventricular wall has now been identified: neuroepithelial cells
probably transform into radial glia, which transform into
astrocyte-like adult stem cells. This integrated view of
NSCs is a dramatic departure from the view that earlyembryonic, late-embryonic and adult NSCs are distinct,
unrelated populations. There are many other basic properties of stem cells that we are just beginning to understand. NSCs often produce intermediate progenitors that
exist transiently and amplify the number of daughter cells
produced by a NSC division. We have also learned that in
the adult brain, oligodendrocytes are produced not just by
restricted progenitors but also by astrocytes residing in a
stem cell niche. It has been speculated that these astrocytes or their progeny play a role in brain tumor formation.
In this review, we will discuss some of these recent
advances and important questions that remain in the
field. Particular attention will be given to the murine
brain, where much of the work was done.
Primary progenitors
The CNS begins as a sheet of cells made up of primary
progenitors known as neuroepithelial cells. The edges of
this sheet fold together to form the neural tube, the fluidfilled center of which later becomes the ventricular system and spinal canal. Neuroepithelial cells are radially
elongated and contact both the apical (ventricular) and
basal (pial) surfaces (Figure 1a). They divide at the
ventricular surface, forming a ventricular zone, but pull
their nucleus toward the pial surface during interphase.
Initially, neuroepithelial cells divide symmetrically to
increase the pool of stem cells but later divide asymmetrically, generating a stem cell that remains in the ventricular zone and a daughter cell that migrates radially
outward [1]. The accumulation of daughter cells thickens the developing brain and radially stretches neuroepithelial cells.
By the onset of neurogenesis, neuroepithelial cells were
thought be replaced by a different NSC: the radial glial
cell [2]. Like neuroepithelial cells, radial glial cells
divide in the ventricular zone and maintain contact
with the pial surface via a radially projecting basal process
(Figure 1b). Since they share many characteristics
(reviewed in [3,4]), it is likely that neuroepithelial
cells transform directly into radial glial cells, although
this has not been shown experimentally. Though it is
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2 Cell differentiation
Figure 1
Neural stem cells (NSCs) and their progeny in the developing forebrain. The NSCs (shown in blue) of the lateral ventricular wall change their
shape and produce different progeny as the brain develops. They begin as neuroepithelial cells and transform into radial glial cells, which mature into
astrocyte-like cells. NSCs maintain contact with the ventricle, into which they project a primary cilium. The potential of an individual stem cell in vivo is
not known and the progeny shown in this schematic are produced by the NSC population. Stem cells produce progeny either directly or via an
intermediate progenitor (shown in green), which has been either included or omitted for clarity. Different types of progeny may be produced by different
intermediate progenitors, although just one is shown here. (a) At early developmental stages the CNS is a tubular structure. It is made up of
neuroepithelial cells, which divide symmetrically at the ventricular surface to expand the stem cell pool. At this time, some early-born neurons such as
Cajal-Retzius cells are produced. (b) Neuroepithelial cells probably differentiate into embryonic radial glial cells, which divide to generate striatal
neurons and oligodendrocytes either directly or via an intermediate progenitor in the subventricular zone (SVZ). The radial processes of radial
glial cells support the migration of neuroblasts (shown in red). (c) Radial glial cells persist in the neonatal brain, where they generate oligodendrocytes,
olfactory bulb interneurons, and ependymal cells. They also generate astrocytes, some of which remain stem cells in the adult. (d) In the adult brain,
neurogenic astrocytes often retain a radial process and contact both the ventricle and the basal lamina of blood vessels. They generate
oligodendrocytes and olfactory bulb interneurons. Stri, striatum; VZ, ventricular zone.
unclear whether a given radial glial cell can produce the
multitude of cell types present in the brain, we know that
individual radial glial cells can generate neurons and that
as a population they are the principal, if not the only,
primary progenitor of the embryonic mammalian forebrain [2]. In mammals, radial glial cells disappear from
the brain soon after birth, but in many species they persist
Current Opinion in Cell Biology 2006, 18:1–6
into adulthood. A subset of radial glial cells remain
neurogenic in adult songbirds [5], lizards [6], turtles [7]
and fish [8]. In mammals, the role of the NSC is filled by a
closely related astrocyte-like cell.
There is now a general consensus that adult mammalian
NSCs have many astrocytic characteristics, such as the
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Neural stem cells in mammalian development Merkle and Alvarez-Buylla
expression of glial fibrillary acidic protein (GFAP)
[9,10,11]. Neurogenic astrocytes are principally found
in two regions: the subventricular zone of the lateral wall
of the lateral ventricle (Figure 1d) and the subgranular
zone of the dentate gyrus of the hippocampus. The
astrocytic nature of NSCs has been confirmed in work
in which GFAP+ cells were conditionally ablated in the
adult mouse brain, resulting in an almost complete loss of
neurogenesis [10,11]. By contrast, there is no support for
the claim that the ependymal cells lining the lateral
ventricle are stem cells. Ependymal cells are post-mitotic
and are not generated in the adult [12] even if stimulated
to proliferate with exogenous growth factors [13].
Since radial glial cells and subventricular zone astrocytes
share many properties, it has been hypothesized that they
belong to the same lineage [14]. In particular, radial glial
cells of the neonatal lateral ventricular wall (Figure 1c)
occupy the same region as the astrocytic stem cells of the
adult subventricular zone (Figure 1d). This hypothesis
was confirmed in a recent study in which radial glial cells
were specifically labeled using a Cre-lox-based strategy
[15]. This work showed that labeled radial glial cells
generate neurons, oligodendrocyes, ependymal cells and
parenchymal astrocytes, as well as subventricular zone
astrocytes that act as NSCs both in vivo and in vitro. Radial
glial cells may directly transform into subventricular zone
astrocytes, since some labeled subventricular zone cells
retain a radial process and express GFAP [15]. In
summary, the current evidence suggests that NSCs gradually transform from neuroepithelial cells to radial glial
cells to astrocyte-like cells (Figure 1).
The recognition that cells of this neurogenic lineage have
glial characteristics has changed our perception of glia
[16–18]. However, we still do not know the fundamental
characteristics that distinguish neurogenic astrocytes
from the vast population of non-neurogenic astrocytes
elsewhere in the brain. It may be possible to identify and
purify these two populations using a combination of
astrocytic markers and markers that are enriched in adult
stem cells. Comparing the gene expression profiles of
these purified populations may shed light on the molecular basis of stem cell behavior.
Intermediate progenitors
Primary NSCs persist in the ventricular zone of the
developing brain through asymmetric self-renewing divisions. Intermediate progenitors, on the other hand, divide
symmetrically in a region just above the ventricular zone
known as the subventricular zone [1,19,20]. This division in the subventricular zone amplifies the number of
cells produced by a given NSC division and may be an
important determinant of brain size, since species with
larger brains have a larger pool of intermediate progenitors [21]. We have learned much about intermediate
progenitors from time-lapse imaging studies, which reveal
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3
the dynamic appearance and behavior of NSCs and their
progeny.
Haubensak and colleagues used time-lapse imaging to
follow cells expressing GFP under the Tis21 promoter,
which is specifically active in neurogenic cells. Labeled
cells were present not only in the ventricular zone but also
in the subventricular zone or basal ventricular zone from
the beginning of neurogenesis. They found that primary
NSCs divide asymmetrically in the ventricular zone while
intermediate progenitors divide symmetrically in the
subventricular zone [1]. This conclusion is supported
by an earlier study by Noctor and colleagues, who followed cells in the developing cortex expressing high
levels of cytoplasmic GFP. This allowed detailed morphological analysis of both parent and daughter cells, and
revealed a curious phenomenon. When intermediate
progenitors reach the subventricular zone, they send
out numerous processes before they divide symmetrically, as if sensing local factors [19].
Environmental factors do indeed influence adult NSCs
and intermediate progenitors. In the subventricular zone,
these cells are also known as type B and type C cells,
respectively. Among the many factors thought to regulate
neural progenitors (reviewed in [22–24]) are, unexpectedly, neurotransmitters. Synaptically released dopamine
stimulates C cell proliferation via the D2 receptor [25].
On the other hand, B cells are inhibited by g-aminobutyric acid (GABA) non-synaptically released from newly
born neurons in the subventricular zone [26].
While it is unclear whether C cells are specified by
environmental cues or by their parent NSC, it is clear
that they are a heterogeneous population. Whereas most,
if not all, adult C cells express the transcription factor
Mash1 [27] and many C cells produce neuroblasts, some
express Olig2 and appear to produce oligodendrocytes
[28,29] (Figure 1d). Olig2 is a basic helix–loop–helix
transcription factor required for oligodendrocyte and
motor neuron production. Recently, it has been shown
to induce the production of oligodendrocytes [28,30] and
perhaps astrocytes [30] in the postnatal subventricular
zone. Olig2+ C cells may be derived from a subset of
subventricular zone astrocytes that express PDGFRa, a
receptor for platelet-derived growth factor (PDGF) [31].
PDGF stimulates the proliferation of the widely dispersed but glial-restricted oligodendrocyte precursor cells
(OPCs) [32].
Interestingly, PDGFRa+ cells in the subventricular zone
hyperproliferate in vivo in response to exogenous PDGF
and form tumor-like masses of intermediate progenitorlike cells, many of which are Olig2+ [31,33]. Many
human brain tumors express Olig2 [34] and have overactive PDGF signaling [35]. These findings are of particular interest since it has been postulated that brain
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4 Cell differentiation
tumors are propagated by a cancerous ‘tumor stem cell’
[36]. The precursor to the tumor stem cell has not been
identified, but it may be an NSC or intermediate progenitor. NSCs that have acquired tumor suppressor gene
mutations are poised to hyperproliferate in response to a
second insult [37,38] and brain tumors are frequently
found near neurogenic niches [39]. Understanding the
role of neural progenitors in tumor formation may lead to
more effective treatment for brain tumors and uncover
the mechanisms that regulate stem cells in the normal and
diseased brain.
The developing neural stem cell
Mammalian NSCs produce different cell types at different points in development. The degree to which older
stem cells retain the ability to generate earlier-born cell
types remains a fundamental question since certain NSCs
might be used to replace brain cells lost in trauma or
disease. To answer this question, we must first understand how NSCs change over time and discover the
mechanisms underlying these changes.
Over the course of development, NSCs change their
morphology and produce different progeny, but also
change their gene expression profiles [40]. Though some
genes are common to both young and old NSCs, others
are expressed only at certain time points. Temporally
specific genes may coordinate an intrinsic developmental
program, since progenitors grown in culture produce
certain progeny at certain times, much like progenitors
in vivo [41]. This program seems to run forwards, but not
backwards. After several days in vitro, cortical progenitors
are unable to produce earlier-born cell types even when
co-cultured with younger progenitors [41], suggesting
that NSCs cannot be respecified by environmental cues.
This phenomenon has been described in fruit flies [42]
and in the vertebrate retina and CNS [43] where NSCs
become unresponsive to the environmental cues that
specified them earlier.
Such commitment, or resistance to respecification, can be
tested by challenging NSCs with heterochronic or heterotopic transplantation. Recent work shows that postnatal
cerebellar progenitors only give rise to postnatally born
cell types when transplanted into the embryonic brain,
whereas transplanted embryonic progenitors give rise to
all appropriate cell types [44]. This finding holds true
even when the progenitors are grown in vitro before
transplantation [45]. These studies confirm the classic
work in ferrets showing that cortical progenitors are
increasingly committed over time [46].
The mechanisms of mammalian NSC commitment are
largely unknown, but may include DNA and histone
modification and/or changes in transcription factor
expression and chromatin structure (reviewed in
[47,23]). Our molecular understanding of invertebrate
Current Opinion in Cell Biology 2006, 18:1–6
stem cell specification and commitment is based on our
identification of their stem cell lineage. Now that the
mammalian NSC lineage is known, perhaps similar
advances can be made in vertebrate stem cell biology.
To understand how the potential of lineally related stem
cells changes over time, one could label individual NSCs
at different developmental stages and trace their progeny
in vivo. Alternatively, NSCs could be labeled in the early
embryo, isolated after defined time points, and either
transplanted or grown in culture. At the same time points,
the gene expression profiles of these NSCs could be
determined and correlated with their potential. Such
approaches would advance our understanding of the
molecular basis of NSC specification and commitment.
This knowledge is essential to effectively design and use
NSC-based therapies.
Conclusions and perspectives
Though recently we have greatly advanced our understanding of mammalian stem cells, there are still many
unanswered questions. What is the in vivo potential of a
NSC, and how does it differ from what we see in vitro?
What distinguishes a neurogenic astrocyte from an astrocyte elsewhere in the brain? What factors permit a cell to
continue acting as a stem cell? What factors specify NSCs,
and what mechanisms are responsible for their commitment? Is their commitment reversible? Can NSCs be
induced to generate a different repertoire of cell types?
To answer these questions, it is important to have a solid
grasp of NSC identity and behavior. The identification of
the neural stem cell lineage and the intermediate progenitors they produce is an important step in this direction.
Acknowledgements
We apologize that many excellent papers were not included in this review
due to space constraints. Many thanks to KX Probst for his help with
illustration, and to RA Ihrie and SC Noctor for their valuable comments that
improved this manuscript. This work is supported by the National Institutes
of Health (NS28478) and by a generous gift from Frances and John Bowes.
FTM. is supported by a fellowship from the National Science Foundation.
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Current Opinion in Cell Biology 2006, 18:1–6
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6 Cell differentiation
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at different time points and the progressive loss of progenitor potential.
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This paper convincingly shows that cortical progenitors have an intrinsic
developmental program which progresses in vitro as well as in vivo. Cells
isolated from older animals and cultured with younger cells were unable
to adopt the greater plasticity of their younger neighbors, suggesting that
the restriction in stem cell potential is irreversible, at least by factors
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Please cite this article in press as: Merkle FT, and Alvarez-Buylla A, Neural stem cells in mammalian development, Curr Opin Cell Biol (2006), doi:10.1016/j.ceb.2006.09.008