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REVIEW ARTICLE

CELLULAR NEUROSCIENCE
published: 27 November 2014
doi: 10.3389/fncel.2014.00396

Neurogenesis in the embryonic and adult brain: same


regulators, different roles
Noelia Urbán * and François Guillemot *
Department of Molecular Neurobiology, MRC National Institute for Medical Research, London, UK

Edited by: Neurogenesis persists in adult mammals in specific brain areas, known as neurogenic
Jens Christian Schwamborn,
niches. Adult neurogenesis is highly dynamic and is modulated by multiple physiological
University of Luxembourg,
Luxembourg stimuli and pathological states. There is a strong interest in understanding how this
Reviewed by: process is regulated, particularly since active neuronal production has been demonstrated
Tao Sun, Cornell University Weill in both the hippocampus and the subventricular zone (SVZ) of adult humans. The
Medical College, USA molecular mechanisms that control neurogenesis have been extensively studied during
Mikio Hoshino, National Center of
embryonic development. Therefore, we have a broad knowledge of the intrinsic factors and
Neurology and Psychiatry, Japan
extracellular signaling pathways driving proliferation and differentiation of embryonic neural
*Correspondence:
Noelia Urbán and François precursors. Many of these factors also play important roles during adult neurogenesis,
Guillemot, Department of Molecular but essential differences exist in the biological responses of neural precursors in the
Neurobiology, MRC National embryonic and adult contexts. Because adult neural stem cells (NSCs) are normally found
Institute for Medical Research, Mill
in a quiescent state, regulatory pathways can affect adult neurogenesis in ways that have
Hill, London NW7 1AA, UK
e-mail: [email protected]; no clear counterpart during embryogenesis. BMP signaling, for instance, regulates NSC
[email protected] behavior both during embryonic and adult neurogenesis. However, this pathway maintains
stem cell proliferation in the embryo, while it promotes quiescence to prevent stem cell
exhaustion in the adult brain. In this review, we will compare and contrast the functions
of transcription factors (TFs) and other regulatory molecules in the embryonic brain and
in adult neurogenic regions of the adult brain in the mouse, with a special focus on the
hippocampal niche and on the regulation of the balance between quiescence and activation
of adult NSCs in this region.

Keywords: hippocampal neurogenesis, development of the hippocampus, regulation of adult neurogenesis, neural
stem cell quiescence, niche signals in adult neurogenesis

INTRODUCTION neurons migrating to the olfactory bulb in mice) and the SGZ
Neural stem cells (NSCs) in the embryonic and early postnatal contributing neurons to the DG (Eriksson et al., 1998; Spalding
murine brain generate neurons and glia, including astrocytes and et al., 2013; Ernst et al., 2014). The addition of new neurons
oligodendrocytes. The transition of proliferative and multipotent to the complex circuitry of the adult brain is the focus of
NSCs to fully differentiated neurons and glia is called neuroge- intensive research, which is uncovering crucial functions for the
nesis and gliogenesis, respectively. Neurons are generated from newly generated neurons in memory and behavior (Deng et al.,
early embryonic development until early postnatal stages, with 2010). In particular, the integration of adult-born granule cells
only a few neurogenic zones remaining active in the adult (Götz to the hippocampus circuitry confers an extra degree of plasticity
and Huttner, 2005; Ming and Song, 2011; Paridaen and Huttner, that is crucial for the acquisition of certain types of contextual
2014). In contrast, gliogenesis starts during late embryogenesis memory (Jessberger et al., 2009; Sahay et al., 2011). Although
and continues in postnatal stages, with low but widespread pro- adult neurogenesis is an ancient trait, with widespread neuroge-
duction of both astrocytes and oligodendrocytes also occurring nesis occurring, for instance, in 16 different adult brain areas of
throughout the adult brain (Rowitch and Kriegstein, 2010; Gallo zebrafish, the appearance of the DG as a structural and functional
and Deneen, 2014; Guérout et al., 2014). The main neurogenic unit seems exclusive to mammals (Treves et al., 2008; Grandel
regions in the adult murine brain are the subependymal zone and Brand, 2013). This fact, amongst others, has prompted the
of the lateral ventricles, also called ventricular-subventricular idea that hippocampal neurogenesis might be a newly evolved
Zone (V-SVZ) and the subgranular zone (SGZ) of the dentate trait in some species, including humans, aimed to enhance adap-
gyrus (DG) in the hippocampus (Altman and Das, 1965; Doetsch tation to a continuously changing environment (Kempermann,
et al., 1999; Ming and Song, 2011; Fuentealba et al., 2012). 2012).
Both of these neurogenic regions have been shown to also be Significant advances have been made in our understanding
active in the adult human brain, with the V-SVZ thought to of the regulation of mouse adult hippocampal neurogenesis in
contribute new neurons to the striatum (whereas it produces the last few years. Thus, our focus for the rest of the review

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Urbán and Guillemot Embryonic vs. adult hippocampal neurogenesis

will be on the mouse model of neurogenesis. The coordinated opposite is true for adult NSCs, which remain for long periods
action of multiple signals acting on embryonic NSCs gives rise out of the cell cycle, in G0. This is a characteristic that adult
to the vast diversity of neuronal and glial populations that NSCs share with many stem cells in other mature tissues and
populate the mature brain. Embryonic neurogenesis is, thus, one that is crucial to maintain tissue homeostasis and avoid
tightly linked to cell fate specification. In adult neurogenic stem cell exhaustion (Orford and Scadden, 2008; Simons and
regions, however, stem cells are tightly restricted to the gen- Clevers, 2011). The existence of adult neurogenic niches (com-
eration of one (granule neurons of the DG) or a few types plex cellular microenvironments surrounding adult NSCs) is also
of neurons (granule neurons and periglomerular neurons in a characteristic shared with other tissues (Fuchs et al., 2004;
the V-SVZ) (Zhao et al., 2008; Ming and Song, 2011). There- Kuang et al., 2008; Mirzadeh et al., 2008; Ming and Song, 2011;
fore signals and factors that specify subtype identities during Fuentealba et al., 2012; Goldstein and Horsley, 2012). The niche is
development can control more subtle aspects of adult stem cell comprised of diverse cell types and structures, such as astrocytes,
behavior. neurons, axon projections and blood vessels, and one of its main
In recent years, it has become evident that, at the single functions is to create an appropriate environment that keeps the
cell level, stem cells in the embryonic and the adult brain are majority of stem cells quiescent and undifferentiated (Morrison
not as versatile as previously thought. Instead of their classically and Spradling, 2008). The niche also provides a great variety of
attributed multipotency, they appear to be already committed to signals that modulate the behavior of adult stem cells and adjust
the generation of specific types of neural cells (Taverna et al., the production of new cells to the needs of the tissue (Fuchs et al.,
2014). The causes and functions of the emerging heterogeneity 2004; Blank et al., 2008; Faigle and Song, 2013).
of adult NSCs are among the most exciting questions remaining In this review we will consider the role of different extrinsic
to be addressed in the field (DeCarolis et al., 2013; Encinas and intrinsic factors on NSCs, comparing their action during
et al., 2013; Giachino et al., 2014b). In the case of the murine adult hippocampal neurogenesis with that reported in the embry-
V-SVZ, different populations of adult NSCs, also called type-B onic brain or in the adult V-SVZ.
cells, co-exist and give rise to distinct types of periglomerular
cells and granule cells in the olfactory bulb. Different adult EMBRYONIC AND ADULT ORIGIN OF GRANULE CELLS
NSCs are characterized by the differential expression of spe- From a developmental point of view, the generation of the DG
cific transcription factors (TFs), including Nkx2.1, Pax6, Gsx2 is unique. While the V-SVZ is seen as a continuation of the
and Nkx6.2, which also pattern the different domains of the embryonic ventricular zone (VZ) of the telencephalon, the forma-
embryonic telencephalon (Merkle et al., 2007; Brill et al., 2008; tion of the DG involves the generation of a dedicated progenitor
López-Juárez et al., 2013; Merkle et al., 2014). The distinct cell source away from the VZ and in close proximity to the pial
adult NSC populations are located in different regions along surface. This additional proliferative zone remains active during
the V-SVZ and their distinct properties are acquired during postnatal stages and eventually becomes the SGZ, which is the
development (Obernier et al., 2014). Despite the spatial sepa- site of adult hippocampal neurogenesis (Figure 1; Bayer, 1980a,b;
ration of these stem cell populations, all their progeny follow Altman and Bayer, 1990; Pleasure et al., 2000; Khalaf-Nazzal and
the same long migratory path, the rostral migratory stream Francis, 2013; Sugiyama et al., 2013).
(RMS), towards their final destination in the olfactory bulb. In The DG originates from the dentate neuroepithelium (DNE),
the hippocampus, adult NSCs, also called type-I cells or radial also called primary matrix, a part of the VZ of the medial
glial-like cells, generate exclusively granule neurons in the DG. pallium that is in direct contact with the cortical hem (CH)
The migration of granule neurons is very limited, as they set- and becomes clearly distinguishable from embryonic day 14.5
tle, differentiate and integrate into the hippocampal circuitry (E14.5; Figures 1A,B). At late gestational stages, progenitor cells
in the granule cell layer (GCL) located just above the NSC migrate out of the DNE towards the pial side of the medial
from which they originated in the SGZ. While they appear cortex in a process that depends on hem-derived Cajal-Retzius
uniform, adult NSCs in the DG respond to diverse and com- cells (Rickmann et al., 1987; Del Río et al., 1997). These pro-
plex signals, raising the possibility that they are functionally genitors, which consist of a heterogeneous mixture of stem cells
heterogeneous. and neuronal precursors at different stages of differentiation,
Despite their many differences, adult NSCs in the two adult migrate away from the VZ towards the hippocampal fissure,
neurogenic niches share several key characteristics. Neural stem constituting a new migratory progenitor population called the
cells in both V-SVZ and SGZ, like radial glial stem cells in secondary matrix (Figures 1B,C). At the same time, a glial
the embryo, express the molecules GFAP, Nestin and Sox2 and scaffold develops and bridges the fimbria to the pial side of
they directly contact blood vessels. Both NSC populations share the cortex and the hippocampal fissure. Both the glial scaffold
a restricted potential, as just discussed, with each generating a and Cajal-Retzius cells remain present throughout DG devel-
unique neuronal subtype and one type of glia: in the V-SVZ they opment and have essential roles in the migration and organi-
generate neurons and oligodendrocytes, while in the SGZ they zation of dentate precursor cells and granule neurons. Neural
generate neurons and astrocytes. Perhaps the two characteristics progenitors reach the hippocampal fissure, where they accumu-
that distinguish adult NSCs most clearly from their embryonic late and form yet another hub of proliferating cells called the
counterparts are the acquisition of quiescence and their situation tertiary matrix (Figures 1C,D). Granule cells generated during
in a complex and stable cellular niche. While one of the main DG development from precursors of all three matrices, form
features of embryonic NSCs is their high proliferative rate, the the GCL. Its characteristic shape of two blades is dictated by

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Urbán and Guillemot Embryonic vs. adult hippocampal neurogenesis

FIGURE 1 | Development of the mouse hippocampus. Schematic from the CH to the hippocampal fissure and pial surface, directing the
representation of the dorsal telencephalon at different embryonic (E) stages migration of dentate precursor cells. From the HNE, hippocampal neurons
and at birth (P0). The indicated area in each picture corresponds to the (red triangles) are born and migrate along radial glial cells towards their
hippocampal region and is magnified on its right handside (blue squares). location in the hippocampal fields (CA1 and CA3 are shown). (D) At birth the
(A) At E12.5 the presumptive DNE is located between the HNE and the CH, blades of the DG start to form. Granule neurons in the DG (red triangles)
which produces Cajal-Retzius cells (orange), shown lining the pial side of the appear first in the upper blade, below the hippocampal fissure. The
cortex. (B) At E14.5 dentate precursors of the primary matrix (dark blue continuous migration of Cajal-Retzius cells reaches the pial side and promotes
circles) are located in the VZ, and precursor cells start to migrate towards the the formation of the lower blade of the DG. Precursor cells in the primary and
pial side of the cortex forming the secondary matrix. In the VZ of the HNE, secondary matrix will soon disappear, but cells in the tertiary matrix continue
radial glial precursors (depicted in dark blue and triangular body shape) will actively dividing and producing granule neurons through postnatal DG
give rise to hippocampal neurons. (C) At E17.5 the hippocampal fissure is development. HNE, hippocampal neuroepithelium; DNE, dentate
formed and dentate precursor cells migrate to and accumulate there, forming neuroepithelium; CH, cortical hem; VZ, ventricular zone; 1ry, primary matrix;
the tertiary matrix (light blue). Cajal-Retzius cells are also present and follow 2ry, secondary matrix; 3ry, tertiary matrix; DG, dentate gyrus; D, dorsal; M,
the hippocampal fissure. At this stage the glial scaffold (not shown) extends medial; V, ventral; L, lateral.

the Cajal-Retzius cells surrounding the hippocampal fissure and adult NSCs are induced at peri-natal stages in a restricted region
the pial surface (Figure 1D). By early postnatal stages, the ter- next to the ventral-most side of the hippocampus, in close prox-
tiary matrix becomes the only source of dentate progenitors imity to the lateral ventricle. Adult NSCs are induced there by
and granule cells. During the second postnatal week, prolifera- SHH secreted from the amygdala and then migrate to populate
tion in the DG becomes even more restricted and is eventually all regions of the DG (Li et al., 2013). The separate origin of
confined to the SGZ, where NSCs reside throughout adulthood embryonic and adult NSCs in the DG could have important
(Figure 2). implications for the function and regulation of adult hippocampal
One of the most interesting and still partially unresolved neurogenesis.
aspects of DG development is the question of the origin of the
adult NSCs. The classical view is that they originate from the REGULATION OF ADULT NEUROGENESIS
whole length of the DNE, from where GFAP-expressing cells The late maturation of the hippocampus, which spans late embry-
migrate towards the SGZ, side by side with differentiating neu- onic and early postnatal stages, means that the process of DG
ronal precursors (Seri et al., 2004; Li and Pleasure, 2005). These formation and the appearance of NSCs with adult character-
GFAP+ progenitors can give rise to granule neurons from early istics are overlapping processes. It can therefore be difficult to
stages of DG development through adulthood (Seki et al., 2014). distinguish between developmental and adult cues regulating
However, genetic cell lineage tracing of Sonic Hedgehog (SHH)- hippocampal neurogenesis. However, several physiological and
responsive cells has recently challenged this view, revealing that pathological situations, such as physical exercise, task learning,

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Urbán and Guillemot Embryonic vs. adult hippocampal neurogenesis

FIGURE 2 | Adult neurogenesis in the dentate gyrus. neurons. Neural stem cells and IPCs reside in the SGZ, while neuroblasts
(A) Immunohistochemistry for the neuronal marker NeuN showing the and neurons are found in the granule cell layer. Several types of interneurons
structure of the adult hippocampus. (B) Magnification of the DG region in (red) and astrocytes (purple) are located in different regions of the DG, and
(A). (C) Graphic representation of the area marked in (B) depicting the together with granule neurons are essential parts of the adult hippocampal
neurogenic lineage and several elements of the DG niche. The neurogenic niche. Blood vessels throughout the DG and axonal projections in the
lineage consists of quiescent and active NSCs (including horizontal molecular layer (horizontal lines) also contribute to the regulation of adult
astrocytes), IPCs (typeIIa, typeIIb), neuroblasts (typeIII) and granule neurogenesis at different steps of the lineage.

an enriched environment and seizures, have been shown to lineage (Figure 2). The selective death of IPCs, for instance, is a
stimulate neurogenesis specifically in the adult DG (Rolando and major mechanism of regulation of neurogenesis in the DG, with
Taylor, 2014). Although no direct link has been clearly established as many as two thirds of these cells being actively eliminated
between those external stimuli and signaling pathways, numerous by microglia (Sierra et al., 2010, 2014). Therefore, in order to
extracellular signaling molecules, including Bone Morphogenetic understand the effects of signaling pathways and intrinsic factors
Proteins (BMPs), Notch, GABA, WNT, insulin growth factors on neurogenesis, it is crucial to determine the stages in the adult
(IGFs) and SHH, have been shown to regulate the rate of neu- neurogenic lineage at which they act, and the cellular processes
rogenesis in the adult DG (Ming and Song, 2011; Faigle and they regulate. In fact, one of the main difficulties faced by the
Song, 2013). However, due to limitations of in vivo studies, little adult neurogenesis field concerns the scarcity of markers for adult
is known about the mechanisms by which these signals exert NSCs, which are often shared by other cell types (for instance,
their effects. In the adult DG, NSCs generate granule cells via a GFAP marks subpopulations of astrocytes and Nestin is expressed
well characterized cell lineage that includes a succession of transit by early intermediate progenitors). This problem is only more
amplifying or intermediate progenitor cells (IPCs), characterized evident in the case of distinguishing quiescent from activated
by rapid divisions and the expression of a series of neurogenic adult NSCs, in which case there is an absolute lack of specific
TFs (Figure 2; Hsieh, 2012). Extrinsic stimuli can affect the markers apart from the use of cell cycle genes. This issue has been
proliferation and survival of NSCs but also of IPCs (typeIIa and partly addressed in a recent report in which an unbiased approach
typeIIb) or differentiating neuroblasts (typeIII) further along the was used to identify genes differentially expressed by activated

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Urbán and Guillemot Embryonic vs. adult hippocampal neurogenesis

and quiescent adult NSCs isolated from the V-SVZ (Codega The complete loss of BMP signaling results in the absence of
et al., 2014). This work demonstrates that the quiescent state is medio-dorsal structures, including the choroid plexus and the
a much more complex state than simply the lack of proliferation CH, resulting in the absence of the hippocampus (Cheng et al.,
markers, as the list of differentially expressed genes is enriched 2006; Fernandes et al., 2007). Once the CH is formed however,
in genes related to very diverse cellular processes, such as lipids BMPs do not seem to be necessary any longer for specification
metabolism, signaling or adhesion. This quiescence signature is of hippocampal cell identities (Hébert et al., 2002). The effects
shared by adult quiescent stem cells from other organs, such that BMPs exert on neural precursors are very diverse, possibly
as the blood, muscle or intestine (Cheung and Rando, 2013; due to the different activities of type 1 BMP receptors (BMPR-I),
Codega et al., 2014). It is thus likely that many of the general including BMPR-Ia, which promotes proliferation in the embry-
characteristics of quiescent stem cells will be shared between DG onic telencephalon, and BMPR-Ib, which induces cell cycle arrest
and SVZ, although no studies on the expression profile of adult and differentiation (Panchision et al., 2001).
DG NSCs have been performed to date. In the adult DG, BMPs are indispensable for the maintenance
Ageing of the brain is marked by a major decrease in the of the quiescent state of NSCs (Mira et al., 2010). Bone Mor-
number of new neurons generated in the DG. This decrease phogenetic Proteins are chronically secreted by granule neurons
has been attributed both to a reduction of the NSC pool and and by NSCs themselves, and several BMP inhibitors, including
to an increased state of quiescence of the remaining stem cells Noggin and Chordin, are also present in the hippocampal niche
(Lugert et al., 2010; Encinas et al., 2011; Jaskelioff et al., 2011; (Scott et al., 2000; Fan et al., 2003; Bonaguidi et al., 2005, 2008).
Seib et al., 2013). The possibility to increase neurogenesis in Loss of BMP signaling by deletion of the BMPR-Ia receptor
ageing mice by activating the quiescent stem cell pool is currently subunit leads to an over-activation of adult NSCs that ultimately
the focus of intensive research. In this regard, it was recently depletes their population (Mira et al., 2010). Bone Morphogenetic
shown that systemic factors from young animals can re-activate Proteins can also induce quiescence in NSCs in culture, providing
neurogenesis in aged mice (Katsimpardi et al., 2014). However, a useful model to study in depth the molecular pathways reg-
disruption of quiescence signals can lead to a short-lived increase ulating stem cell behavior (Mira et al., 2010; Sun et al., 2011;
in neurogenesis, followed by a sharp decrease caused by a loss of Martynoga et al., 2013). In this in vitro system, proliferating
quiescent NSCs (Ehm et al., 2010; Mira et al., 2010; Song et al., NSCs treated with BMP4 in combination with FGF2 rapidly
2012). Assessing precisely how factors and signals affect stem exit the cell cycle and can be maintained for several weeks in
cell behavior will be vital to understand their long-term effects a state of reversible cell cycle arrest, in which cells retain their
on adult neurogenesis. Lineage tracing and particularly clonal proliferation and neurogenic potentials (Martynoga et al., 2013).
analysis of NSCs in the DG have begun to provide evidence of Bone Morphogenetic Proteins can also promote the expression of
the great diversity of responses of adult NSCs to stimuli, which astrocytic genes in vitro, raising the possibility that they induce
can affect both their proliferation and differentiation potentials some of the astroglial features of adult NSCs (Gross et al., 1996;
(Bonaguidi et al., 2011; Dranovsky et al., 2011; Song et al., Sun et al., 2011). Bone Morphogenetic Proteins are necessary not
2012). only for the quiescence of NSCs, but also for the differentiation
and maturation of granule cells (Bond et al., 2014). This dual
CORTICAL hem SIGNALS: BMP AND WNT role might be explained by the differential expression of the
The formation of the hippocampus starts in the mouse around BMPR-I receptors. Neural stem cells in the adult DG express
E14 in response to the signals emanating from the CH, a dorso- BMPR-Ia, which is downregulated in IPCs, while neuroblasts and
medial telencephalic structure that acts as an organizer for the neurons express BMPR-Ib (Mira et al., 2010). Therefore, both
hippocampus and the choroid plexus (Grove et al., 1998; Mangale NSCs and neuroblasts receive BMP signals, which they interpret
et al., 2008). The hem is characterized by the active secretion as quiescence and differentiation cues, respectively.
of BMP and WNT molecules and the lack of expression of the The effects of BMP signaling on adult neurogenesis in the V-
TF Lhx2. The crucial role of the hem in the formation of the SVZ are less well understood (Lim et al., 2000; Colak et al., 2008).
hippocampus is demonstrated by both loss and gain of function There is currently no clear evidence supporting a role for BMPs
studies. When the hem fails to form, the hippocampus does not in maintaining the quiescence of V-SVZ stem cells, and the BMP
develop properly (Yoshida et al., 2006), while in Lhx2 mutant inhibitor Noggin does not affect the behavior of V-SVZ-derived
chimeric embryos, the hem-like Lhx2-negative tissue is able to stem cells while it promotes the expansion of DG-derived stem
induce hippocampal gene expression in ectopic areas of the dor- cells in vitro (Bonaguidi et al., 2008).
sal telencephalon (Mangale et al., 2008). Bone Morphogenetic The embryonic CH produces several WNT proteins, including
Protein and WNT signals have critical functions in hippocampal WNT2a, WNT2b, WNT3a and WNT5a, which are instrumental
development, particularly to promote the proliferation of neural for its role as hippocampal organizer. For instance, disruption
precursors (Furuta et al., 1997; Galceran et al., 1999; Lee et al., of WNT3a prevents the formation of the hippocampus, thus
2000; Caronia et al., 2010). In the adult, both signals continue to establishing the absolute requirement for WNTs in hippocampal
be extremely important for NSCs maintenance and differentia- development (Lee et al., 2000). Disruption of Lef1, the main
tion, but their effects are very different, as discussed below. downstream effector of canonical WNT signaling, or of the WNT
Multiple BMPs (BMP4, BMP5, BMP6 and BMP7) are pro- receptor Lrp6, also causes severe hippocampal defects (Galceran
duced early on by the telencephalic roof plate and later by the et al., 1999; Yoshida et al., 2006). Moreover, ectopic expression
CH (Furuta et al., 1997; Grove et al., 1998; Hébert et al., 2002). of Lef1 is sufficient to specify particular hippocampal domains,

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Urbán and Guillemot Embryonic vs. adult hippocampal neurogenesis

thus demonstrating that WNT activation is sufficient to confer precursor specification or differentiation, but rather in broader
hippocampal identity (Machon et al., 2007). WNTs are also decisions, including the regulation of neural lineage commitment,
involved in the formation of the glial scaffold, which is required the tempo of neuronal and glial generation and the maintenance
during DG development for the migration of neural precursor of stem cells. Notch receptors and ligands are broadly expressed
cells from the VZ in the medial pallium to their final location in during all stages of development of the hippocampus (Pleasure
the hippocampus (Zhou et al., 2004). et al., 2000). Loss of the essential Notch signaling component
WNT signaling also plays a role in postnatal and adult neuro- RBPJk in the developing brain results in proliferation defects and
genesis (Zhang et al., 2011; Ortiz-Matamoros et al., 2013; Varela- premature differentiation of embryonic NSCs (Imayoshi et al.,
Nallar and Inestrosa, 2013). WNTs are secreted by astrocytes 2010). Similarly, loss of RBPJk or of the Notch ligand Jagged1
and by stem cells and are therefore thought to act both in a during hippocampal development leads to defects in proliferation
paracrine and an autocrine manner (Lie et al., 2005; Qu et al., and stem cell maintenance, although the formation of the DG is
2010; Okamoto et al., 2011). WNTs can directly induce neu- not prevented (Breunig et al., 2007; Lavado and Oliver, 2014).
rogenic genes such as Neurog2, NeuroD1 and Prox1 in inter- Therefore, the main function of the Notch pathway in embry-
mediate progenitors, and they have a well-established role in onic NSCs is to maintain their proliferative and undifferentiated
synapse formation and the maturation of adult-born neurons state.
(Kuwabara et al., 2009). Inhibition of canonical WNT signal- High levels of Notch signaling, assessed by the expression of
ing in the DG in vivo has adverse effects on the performance the Notch targets Hes1 and Hes5, are present in NSCs in the
of mice in DG-dependant behavioral tests, suggesting that this adult DG (Imayoshi et al., 2010; Lugert et al., 2010). The main
pathway regulates adult hippocampal neurogenesis. In addition Notch ligand is Jagged1, which is expressed both by the niche
to promoting neuronal differentiation and maturation, several astrocytes and by IPCs, although other ligands, such as Dll1, Dll3
in vitro studies have shown that canonical WNT signaling also or Dll4, and other cellular sources, such as endothelial cells and
affects the proliferation of hippocampal progenitors (Lie et al., NSCs themselves, could also contribute to maintaining Notch
2005; Varela-Nallar and Inestrosa, 2013). Moreover, a recent activity in NSCs (Stump et al., 2002; Lavado and Oliver, 2014).
genetic analysis of the WNT inhibitor secreted frizzled related The interaction between Jagged1 on IPCs and Notch receptors on
protein 3 (SFRP3) in the DG in vivo, also provides support NSCs has been proposed to function as a feedback mechanism
for a role of WNT signaling in adult NSC activity. Loss of maintaining NSC quiescence. Elimination of the IPC population
SFRP3, which is normally tonically secreted by granule cells, leads to an initial increase in NSC activation and IPC production
resulted in excessive proliferation of NSCs and the loss of the followed by the exhaustion of the stem cell pool (Lavado et al.,
quiescent stem cell pool (Jang et al., 2013). Neuronal activity 2010; Hodge et al., 2012). The same sequence of events also takes
was shown to decrease the production of SFRP3 by granule place when Notch signaling is ablated cell autonomously in NSCs
cells, thus establishing a molecular link between neuronal activity by deletion of the Notch1 receptor or of RBPJk (Ables et al., 2010;
and neurogenesis in the DG. In another study, deletion of the Ehm et al., 2010; Lavado and Oliver, 2014).
WNT inhibitor Dickkopf-related protein 1 (Dkk1) from granule The effects of Notch on adult neurogenesis are context-
neurons was sufficient to restore hippocampal neurogenesis in dependent, as also reported in other adult stem cell niches
old mice (Seib et al., 2013). This finding demonstrates that the (Mourikis and Tajbakhsh, 2014). In particular, signaling through
decline in neurogenesis in aged mice results, at least in part, Notch1 appears to have different functions in the DG and the V-
from the increased quiescence of NSCs, and not only from the SVZ. Loss of Notch1 in the DG leads to a significant decrease
diminution of the stem cell pool, and suggests that this decline in the number of NSCs, while Notch1 deletion in the V-SVZ
can be reversed. impairs the proliferation of NSCs without affecting their total
Because BMP and WNT signals act at multiple steps of the number (Ables et al., 2010; Basak et al., 2012). The role of
neurogenic lineage during both embryonic and adult neuroge- Notch signaling in adult neurogenesis has also been studied in
nesis, it is difficult to assess their specific contribution to the zebrafish, where, as in the mammalian hippocampus, it is essential
regulation of NSCs. Nevertheless, current evidence indicates that to keep stem cells quiescent (Chapouton et al., 2010, 2011). In
WNT signaling maintains its pro-proliferative function from zebrafish, different Notch receptors appear to operate at different
embryonic to adult NSCs and that modulation of its activity by steps of neurogenesis and to regulate different properties of stem
WNT antagonists secreted by surrounding granule neurons is cells, with Notch3 activity maintaining quiescence and Notch1
a critical aspect of the regulation of NSCs by the hippocampal being required to prevent premature stem cell differentiation
niche. In contrast, BMP signaling through BMPR-Ia changes (Alunni et al., 2013). In the mammalian brain as well, diver-
drastically its function from embryonic neural precursors, where gent functions of the different Notch receptors might contribute
it is mitogenic, to adult DG stem cells where it is a potent inducer to the heterogeneity of the responses of adult progenitor cells
of quiescence. to Notch ligands (Shimizu et al., 2002; Giachino and Taylor,
2014). It is worth noting that perturbing Notch signaling has
NOTCH SIGNALING both cell autonomous and cell non-autonomous consequences,
The functions of Notch signaling during embryonic brain devel- which complicates the dissection of its specific roles in adult
opment have been extensively reviewed elsewhere (Kageyama neurogenesis.
et al., 2008; Imayoshi and Kageyama, 2011). During development A tantalizing hypothesis for the mechanism underlying Notch
of the hippocampus, Notch does not seem to be involved in neural function in stem cell quiescence comes from embryonic data

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Urbán and Guillemot Embryonic vs. adult hippocampal neurogenesis

showing that the levels of Hes proteins and proneural bHLHs DG present both proliferation and differentiation defects, and
oscillate in neural precursor cells (Imayoshi et al., 2013). Hes although Ascl1 is also expressed by progenitor cells during DG
proteins are bHLH TFs that are induced by Notch activity and morphogenesis, it does not compensate for the loss of Neurog2,
act as potent repressors of gene expression, and proneural bHLH in contrast with what is observed in the embryonic telencephalon
genes are amongst their main targets (Imayoshi and Kageyama, (Nieto et al., 2001; Galichet et al., 2008). In addition, the glial
2014). Hes transcripts and proteins oscillate with a frequency scaffold is disorganized in the Neurog2 mutant DG, suggesting
of 2–3 h, because Hes proteins repress their own transcription that progenitor migration is also disrupted (Galichet et al., 2008).
and because this repression is only transient due to their short The disorganization of the glial scaffold and atrophy of the DG
half-lives (Shimojo et al., 2008; Imayoshi et al., 2013). The oscil- are reminiscent of the phenotypes observed in WNT mutant
lation of Hes proteins drives in opposite phase the oscillation embryos, and since Neurog2 expression has been reported to be
of their targets, including the proneural proteins Neurog2 and regulated by WNT signaling in the embryonic brain, Neurog2
Ascl1 (Shimojo et al., 2008; Imayoshi et al., 2013). Ascl1 has might act as an effector of WNT signaling during DG forma-
been shown to have two opposing roles in embryonic neuroge- tion (Hirabayashi et al., 2004; Zhou et al., 2004; Galichet et al.,
nesis, promoting progenitor proliferation and driving their cell 2008).
cycle exit and differentiation (Castro et al., 2011). Interestingly, In the adult V-SVZ, Neurog2 is expressed by a subset of IPCs
the oscillating expression of Ascl1 promotes the proliferation that differentiate into glutamatergic interneurons (Brill et al.,
of neural progenitors, while its stable expression instead drives 2009). Neurog2 is also expressed transiently by a subset of Tbr2
differentiation (Imayoshi et al., 2013). The mechanisms that positive IPCs in the DG (Hodge et al., 2008). NeuroD1, a target
convert different Ascl1 dynamics into the activation of differ- of Neurog2 in the embryonic cerebral cortex, is expressed in neu-
ent gene expression programmes, promoting proliferation and roblasts in the SGZ and might therefore be induced by Neurog2
differentiation, respectively, remain unknown. Whether Hes and in the DG lineage (Hodge et al., 2008). However, the function of
Ascl1 proteins also oscillate in adult progenitors has not yet been Neurog2 in DG neurogenesis has not yet been reported.
established. Adult NSCs express high levels of Hes proteins, but The T-box TF Tbr2 is another principal regulator of
an initial reduction in the amount of Notch signaling might embryonic neurogenesis, which promotes the generation and
initiate their oscillatory expression, which would thus trigger the proliferation of intermediate progenitors that give rise to
oscillation of Ascl1 expression and the proliferation of NSCs. pyramidal glutamatergic neurons in the developing cerebral
Subsequently, a complete loss of Notch activity in IPCs would cortex (Englund et al., 2005; Arnold et al., 2008; Sessa et al.,
stabilize Ascl1 expression and promote neuronal differentiation. 2008). In the developing DG Tbr2 is expressed, like Neurog2, by
Several observations support such a scenario. Ascl1 expression is proliferating progenitor cells in all three matrices (Hodge et al.,
indeed increased upon loss of RPBJk in NSCs, showing that also in 2012). Ablation of Tbr2 prevents the generation of IPCs and
the adult DG, Notch signaling suppresses its expression (Andersen granule neurons while increasing the proliferation of stem cells
et al., 2014). Differences in the intensity of Notch signaling have in the developing DG, indicating that Tbr2 is necessary for the
been singled out as possible causes of the heterogeneity in adult transition from stem cells to late, differentiating IPCs (Figure 2).
NSC behavior (Giachino and Taylor, 2014). Moreover, Ascl1 Tbr2 has been proposed to exert its functions through direct
expression in adult NSCs is excluded from quiescent NSCs and down-regulation of the stem cell TF Sox2 (Hodge et al., 2012).
confined to about a third of activated NSCs, suggesting that Ascl1 In addition, Tbr2 is expressed by hem-derived Cajal-Retzius cells
has indeed a dynamic expression in proliferating NSCs (Andersen and is required for their migration, so defects in the distribution
et al., 2014). Further analysis will determine the importance of of Cajal-Retzius cells also contribute to the defects in DG
the interactions between the Notch-Hes pathways and Ascl1 in morphogenesis in Tbr2 mutant mice (Hodge et al., 2013).
regulating the transitions between quiescent and activated NSCs In the adult brain, Tbr2 is also expressed by IPCs in the two
and between NSCs and IPCs. neurogenic regions (Hodge et al., 2008; Roybon et al., 2009).
Elimination of Tbr2 from NSCs blocks the production of late
NEUROGENIC TFs: Neurog2, Tbr2 AND Prox1 IPCs and granule neurons, similar to the phenotype observed in
Neurog2 is a bHLH TF with proneural activity in the embryonic the developing DG. Interestingly, the loss of Tbr2 also results in
brain, as it promotes the neuronal commitment of multipotent an increase in the proliferation of NSCs and their expression of
stem cells and induces the expression of other genes involved Ascl1 (Hodge et al., 2012). This could be explained by a non-cell
in neuronal differentiation, such as the NeuroD family of TFs autonomous induction of NSC quiescence by IPCs through Notch
(Seo et al., 2007; Wilkinson et al., 2013). Neurog2 also has a signaling, as shown in the case of Prox1 mutant mice (see below),
prime role in the specification of glutamatergic neurons in the although a more direct role of Tbr2, which is expressed by a small
embryonic brain (Schuurmans et al., 2004; Berninger et al., 2007; subset of NSCs, is not ruled out (Hodge et al., 2008, 2012).
Wilkinson et al., 2013). During DG development, precursor cells Prox1 is a homeobox TF expressed by multiple types of
in all proliferative matrices express Neurog2 (Pleasure et al., neuronal progenitors and postmitotic cells, including newly
2000; Galichet et al., 2008). Neurog2 has an essential role in born granule cells in the tertiary matrix of the developing DG
the formation of the DG, as shown by the analysis of Neurog2 (Oliver et al., 1993; Li et al., 2009). Prox1 is often used as a
null mutant mice, that present at birth a severely atrophic DG, marker of the dentate granule neuron lineage, although it is
with an upper blade greatly reduced in size and a lower blade also expressed at low levels in some hippocampal interneurons
missing (Galichet et al., 2008). Progenitors in the Neurog2 mutant (Rubin and Kessaris, 2013). Analysis of Prox1 null mutant mice

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Urbán and Guillemot Embryonic vs. adult hippocampal neurogenesis

has shown that Prox1 is essential during DG development for the mutant mice are discussed in greater detail in the following
proliferation of neuronal progenitors and for the specification of paragraphs.
granule cells (Lavado et al., 2010). Remarkably, deleting Prox1 Transcription factors of the Nuclear Factor 1 (NFI) family have
specifically in post-mitotic granule neurons results in a change in been implicated in the generation of neuronal and glial cells dur-
cell identity to that of CA3 pyramidal neurons (Iwano et al., 2012). ing hippocampal development. In particular, NFIX is expressed at
In the adult DG, Prox1 is also expressed by late IPCs and high levels in the DNE, the primordium of the future DG, as early
its expression is maintained in mature granule neurons (Oliver as E14 and NFIX null mutant mice present severe defects in DG
et al., 1993; Galeeva et al., 2007; Karalay et al., 2011). Conditional formation (Campbell et al., 2008; Heng et al., 2014). Neuronal
deletion of Prox1 in the adult DG impairs the proliferation, and glial differentiation are delayed in NFIX mutants, and these
survival and differentiation of DG IPCs (Lavado et al., 2010). animals present a decrease in the number of Prox1+ granule neu-
Even though Prox1 is not expressed in NSCs, the loss of Jagged1- rons as well as a disorganization of the glial scaffold and a defect
expressing IPCs results in the exhaustion of the NSC pool, due in DG morphogenesis (Heng et al., 2014). NFIX mutant mice
to a decrease in Notch signaling in the stem cells (Lavado et al., survive until P20, and by that time NSCs are present at a normal
2010). density in the DG but are abnormally located, with misplaced cell
Both Tbr2 and Prox1 conserve the same roles in the gener- bodies and misaligned basal processes (Martynoga et al., 2013).
ation of granule cells during embryonic/postnatal hippocampal The abnormal positioning of NFIX mutant NSCs is accompanied
development and in the adult DG. This suggests that the same by an increase in their proliferation rate, suggesting that they are
genetic programme involving the same key TFs (Neurog2 > Tbr2 unable to enter or maintain quiescence. Transcriptome analysis of
> NeuroD1 > Prox1) drives the differentiation of IPCs into NFIX-inactivated NSCs in the BMP-induced cell culture model
glutamatergic cells in the DG from development to adulthood of NSC quiescence discussed before, revealed that NFIX regulates
(Hodge et al., 2008, 2012). However this does not hold true for a large fraction (about one third) of the genes that are regulated
factors acting earlier in the granule cell lineage as discussed in the between the quiescent and activated NSC states. Interestingly, a
following section. significant fraction of NFIX-regulated genes control cell adhesion,
cell motility or extracellular matrix production (Martynoga et al.,
2013). Thus, NFIX might be required for NSCs to correctly locate
THE TRANSITION FROM POSTNATAL TO ADULT to the SGZ and interact with the different components of the DG
NEUROGENESIS: NFIX, Tlx, CcnD2 AND AScl1 niche. In its absence, NSCs may not receive the signals required
Granule neurons in the adult DG are exclusively generated by to remain quiescent. NFIX function in adult neurogenesis has not
NSCs located in the SGZ. During embryonic and postnatal devel- yet been analyzed.
opment, in contrast, neurons are generated by a heterogeneous Tlx, also known as Nr2e1, is an orphan nuclear receptor
population of precursor cells in the dentate matrices (Figures 1, that is involved in patterning of the embryonic telencephalon.
2). The exact time at which the switch from embryonic to adult Tlx is expressed throughout the telencephalic VZ, except in the
modes of neurogenesis occurs in the DG is still not well defined. dorso-medial region that will give rise to the hippocampus. Tlx
Several independent pieces of evidence suggest that this happens expression remains low in neurogenic regions during late embry-
around the second week of life in mice. At postnatal day 14 onic and postnatal stages and is upregulated only at adult stages
(P14), the blades of the DG are already formed and the source (Monaghan et al., 1995; Shi et al., 2004). Tlx mutant mice present
of new neurons in the DG becomes restricted to the tertiary abnormally small DG and olfactory bulbs, as a result of impaired
matrix, which gradually becomes the SGZ (Pleasure et al., 2000; adult neurogenesis from the SGZ and V-SVZ. The DG of adult
Sugiyama et al., 2013). At the same time, the first presumptive Tlx mutant mice presents deficits in progenitor proliferation and
GFAP- and Nestin-positive NSCs adopt their characteristic loca- in the generation of new neurons, which can be reversed by re-
tion, with the nucleus residing in the SGZ and the basal process expression of Tlx in mutant NSCs (Shi et al., 2004; Zhang et al.,
extending through the GCL (Li and Pleasure, 2005; Martynoga 2008; Niu et al., 2011; Murai et al., 2014). Overexpression of
et al., 2013). The TF NFIX has recently been shown to be required Tlx in the DG of wild-type mice also stimulates neurogenesis
for NSCs to adopt their correct location in the developing DG and enhances learning and memory performances (Murai et al.,
(Martynoga et al., 2013). It is also around the end of the sec- 2014). These studies suggest that Tlx promotes the switch of NSCs
ond postnatal week that specific defects in adult neurogenesis from quiescence to activation, and several downstream pathways
are first noticed in two interesting mouse lines that carry null have been implicated in this activity, including the induction of
mutations in the CcnD2 and Tlx genes (Kowalczyk et al., 2004; WNT signaling and of Ascl1 expression and the dowregulation of
Shi et al., 2004; Ansorg et al., 2012). In these two mutants, BMP signaling (Shi et al., 2004; Elmi et al., 2010; Qu et al., 2010;
the formation and development of the DG during embryonic Qin et al., 2014).
and early postnatal life are relatively normal but during late CcnD2 (Cyclin D2) is a key component of the cell cycle
postnatal stages and throughout adulthood, the stem cells fail to machinery that controls the transition between the G1- and S-
maintain their granule neuron production. Similarly, conditional phases of the cell cycle, together with the other Cyclin D proteins
deletion of the proneural gene Ascl1 results in a complete block (CcnD1 and CcnD3) and the Cyclin-dependent kinases (CDKs;
of adult neurogenesis whereas it is dispensable for embryonic Sherr, 1994; Ekholm and Reed, 2000). During embryonic devel-
and early postnatal neurogenesis in the DG (Galichet et al., 2008; opment, CcnD1 and CcnD2 promote cell cycle progression but
Andersen et al., 2014). The adult neurogenesis defects of these also induce the neuronal differentiation of neural progenitors

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Urbán and Guillemot Embryonic vs. adult hippocampal neurogenesis

(Lukaszewicz and Anderson, 2011; Pauklin and Vallier, 2013). has been shown to directly regulate CcnD2, suggesting that one
Although CcnD genes are structurally very similar and can usually of its roles is to directly promote cell cycle progression of NSCs
substitute for one another functionally, their expression profiles (Andersen et al., 2014).
are distinct. As a result, different CcnD genes are required for Besides its expression in multipotent stem cells and neuronal
the proliferation and differentiation of distinct progenitor pop- progenitors, Ascl1 is also expressed in, and required for the
ulations, and CcnD2 has been shown to be specifically required specification and differentiation of, a subset of oligodendrocyte
for the proliferation of intermediate precursors in the embryonic precursors in both embryonic and adult brains (Parras et al., 2004;
cerebral cortex (Komada et al., 2013). Sugimori et al., 2007; Nakatani et al., 2013). Unexpectedly, overex-
Adult CcnD2 mutant mice present relatively normal brain pression of Ascl1 in IPCs of the DG promotes their differentiation
morphology, but they are 25% smaller than wild-type mice. As in into oligodendrocytes, a cell type normally not generated by this
Tlx mutants, CcnD2 deficient mice present severely reduced rates cell lineage (Jessberger et al., 2008). Why Ascl1 has such different
of neurogenesis in both the V-SVZ and the DG (Kowalczyk et al., activities in the adult DG when analyzed by loss-of-function or by
2004). Interestingly, the requirement for CcnD2 in the prolifera- gain-of-function approaches is currently unclear.
tion of NSCs builds up progressively from early postnatal stages The analysis of NFIX, Tlx, CcnD2 and Ascl1 mouse mutants
and becomes absolutely necessary at 4 weeks of age. By then, the provides strong evidence that the genetic programmes that
DG of CcnD2 mutant mice is almost completely devoid of prolif- promote neurogenesis in the DG during development and in
erating cells and of differentiating neuroblasts, and these defects the adult are distinct. However, only null mutants for NFIX,
persist throughout life (Ansorg et al., 2012). CcnD2 mutant mice Tlx and CcnD2 have been analyzed, and conditional mutant
have been extensively used to study the contribution of adult-born mice will be required to rule out that developmental defects
neurons to memory and behavior. These mice are able to learn are responsible for the adult hippocampal phenotypes. The
spatial tasks known to be dependant on hippocampal functions, similarities between the phenotypes of Tlx, CcnD2, and Ascl1
but they show reduced flexibility in updating previously learned mutants suggest that these genes belong to a common reg-
information, shedding light into the specific functions of new- ulatory pathway operating specifically during adult neuroge-
born cells in the DG (Jaholkowski et al., 2009; Jedynak et al., 2012; nesis to promote stem cell activation. The severity of their
Garthe et al., 2014). Strikingly, CcnD1, which is expressed during mutant phenotypes demonstrates the fragility of the adult neu-
DG development and can promote proliferation and neurogenesis rogenic process. The loss of one of these genes in adult stem
in the adult DG when overexpressed, does not compensate for the cells cannot be functionally compensated while their loss dur-
loss of CcnD2 in the adult DG (Shtutman et al., 1999; Tetsu and ing DG development has milder or no effects, suggesting that
Mccormick, 1999; Kowalczyk et al., 2004; Klein and Assoian, 2008; more robust regulatory mechanisms support embryonic and
Artegiani et al., 2011). postnatal neurogenesis. The similar or different action dur-
Ascl1 is a proneural bHLH TF that has crucial roles in ing embryonic and adult hippocampal neurogenesis of the
the proliferation, neuronal commitment and differentiation of molecules and pathways discussed so far is summarized in
progenitors in the embryonic brain (Bertrand et al., 2002; Castro Table 1.
et al., 2011; Imayoshi and Kageyama, 2014). When overex-
pressed in astrocytes, fibroblasts and other cell types, it also has OTHER SIGNALING PATHWAYS: SHH, IGF AND
the capacity to re-program these cells into neurons (Berninger NEUROTRANSMITTERS
et al., 2007; Yang et al., 2011; Wapinski et al., 2013). Ascl1 is We will briefly discuss here the roles of other key signaling
expressed throughout DG development by progenitor cells in pathways for which specific roles in hippocampal development or
the three matrices, but it is not required for the development in adult neurogenesis have not been reported.
of the DG at embryonic stages (Pleasure et al., 2000; Galichet Sonic Hedgehog signaling has crucial roles in early pattern-
et al., 2008). Moreover, conditional ablation of Ascl1 during ing and cell fate specification in the embryonic brain. Recently,
early postnatal stages does not affect stem cell proliferation, NSCs in the adult DG have been shown to originate from SHH-
suggesting that in its absence, other factors can promote pro- responsive progenitors in the ventral hippocampus (Li et al.,
genitor proliferation in the developing DG (Andersen et al., 2013). Sonic Hedgehog signaling has been implicated in the
2014). proliferation and maintenance of both DG and V-SVZ adult
In the adult brain, Ascl1 remains expressed in intermediate NSCs (Machold et al., 2003; Álvarez-Buylla and Ihrie, 2014).
progenitors as well as in a subset of actively self-renewing stem Although the sources of SHH that regulate V-SVZ and SGZ
cells in the DG and V-SVZ (Pleasure et al., 2000; Parras et al., neurogenesis have not been clearly identified yet, tracing the
2004; Breunig et al., 2007; Kim et al., 2007; Seki et al., 2007; activity of SHH by the expression of the SHH-inducible gene Gli1
Hodge et al., 2008; Pastrana et al., 2009; Lugert et al., 2012). in Gli1nLacZ mice has shown that NSCs in both adult neurogenic
Strikingly, deletion of Ascl1 renders adult NSCs permanently regions as well as a fraction of mature astrocytes express the
quiescent and blocks neurogenesis in both neurogenic niches beta galactosidase reporter protein and therefore receive SHH
(Andersen et al., 2014). Ascl1-deficient NSCs in the adult DG are signals (Ahn and Joyner, 2005; Garcia et al., 2010; Ihrie et al.,
not able to respond to neurogenic stimuli, suggesting that Ascl1 2011; Petrova et al., 2013). Removal of SHH signaling from
is a niche-induced factor that acts at an early step in the switch V-SVZ stem cells by deletion of the receptor Smoothened has
from quiescence to activation. Although the exact mechanisms by revealed that SHH is necessary for the proliferation and long term
which Ascl1 controls this switch remain to be elucidated, Ascl1 maintenance of the stem cells, as well as the subtype specification

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Urbán and Guillemot Embryonic vs. adult hippocampal neurogenesis

of the neurons they generate (Palma et al., 2005; Balordi and in the adult V-SVZ or the DG in rodents (Berg et al., 2013), but
Fishell, 2007; Kim et al., 2007; Ihrie et al., 2011; Petrova et al., few studies have assessed their specific effect on stem cells.
2013; Merkle et al., 2014). In adult DG stem cells, conditional
disruption of primary cilia, which are required for SHH signaling, RADIAL Glia AND ADULT NSCs, POLARITY
decreases the production of IPCs, supporting a role for SHH in The characteristic shape and location of radial glial stem cells
NSC divisions in the DG as well (Breunig et al., 2008; Amador- in the VZ of the embryonic brain, with their apical side in
Arjona et al., 2011). However, a more direct investigation of contact with the brain ventricles and their basal process con-
the role of SHH in adult DG neurogenesis has not yet been tacting the pial surface, are vital to their stem cell function and
performed. cellular behavior (Götz and Barde, 2005; Götz and Huttner, 2005;
Insulin/Insulin Growth Factors (IGFs) signaling has been Malatesta and Götz, 2013). Stem cells in the adult brain present a
shown to stimulate stem cell proliferation and neurogenesis in similar radial morphology. In the DG, NSCs have an apical side
the adult DG, and this pathway has been proposed to mediate the resting in the SGZ and a basal process extending through the
stimulating effect of physical exercise (running) on neurogenesis GCL and branching into the molecular layer (Fuentealba et al.,
(Trejo et al., 2008; Bracko et al., 2012). IGF1, IGF2 and insulin 2012). The marked polarity of radial glial cells in the embryonic
are present in the cerebrospinal fluid but can also reach brain brain has been linked to the reception of distinct signals by
progenitors through the bloodstream (Margolis and Altszuler, different subcellular domains, and to the asymmetric distribu-
1967; Woods et al., 2003). Insulin/IGF signaling involves both the tion of signal transduction components and fate determinants
PI3K/Akt and the MAPK pathways, and the mitogenic activity during cell division (Götz and Huttner, 2005). Although some
of IGF2 in DG NSCs requires Akt activity (Bracko et al., 2012). of these features might be shared by adult NSCs, no study has
IGF/Akt signaling inactivates the TF FoxO3 through phosphory- yet directly examined the interactions of adult NSCs with niche
lation and nuclear exclusion (Calnan and Brunet, 2008; Kenyon, cells in situ, the processing of niche signals or the division of
2010). FoxO3 is expressed by stem cells in the adult DG and V- adult NSCs. Prominin-1 (CD133), for instance, is segregated to
SVZ and is required to maintain their quiescence (Paik et al., 2009; the apical membrane in embryonic radial glia (Weigmann et al.,
Renault et al., 2009). Therefore IGF2 might promote stem cell 1997; Kosodo et al., 2004) and has been shown to promote
activity in the adult DG in part via Akt-mediated inactivation of the generation of plasma membrane protrusions (Röper et al.,
the quiescence factor FoxO3. Interestingly, Akt activity has been 2000; Corbeil et al., 2001; Kosodo et al., 2004). Prominin-1, in
shown to also increase the stability of the Ascl1 protein in the combination with glial markers, has been used to identify and
embryonic brain (Oishi et al., 2009), suggesting that the IGF/Akt sort NSCs from the embryonic brain and from the V-SVZ and
might stimulate NSC proliferation by both inactivating a quies- DG in the adult brain (Pinto et al., 2008; Beckervordersandforth
cence factor (FoxO3) and stabilizing an activation factor (Ascl1). et al., 2010, 2014; Walker et al., 2013). Prominin-1 is also apically
Several neurotransmitters have been shown to influence stem localized in NSCs of the V-SVZ and SGZ, but its distribution
cell behavior in the adult V-SVZ and DG, providing a mechanistic after adult NSC division has not been examined. Similarly, beta-
link between the activity of particular neuronal populations and catenin is associated with the apical membrane in embryonic
the regulation of adult neurogenesis (Berg et al., 2013). The NSCs and is involved in the selection between proliferative and
role of the neurotransmitter GABA (γ-aminobutyric acid) in neurogenic modes of division (Machon et al., 2003; Zechner
the regulation of adult hippocampal neurogenesis has been et al., 2003). Despite the importance of beta-catenin in trans-
the focus of several recent studies (Masiulis et al., 2011; Song ducing WNT signals, how it is distributed amongst daughter
et al., 2012; Giachino et al., 2014a). GABA can signal through cells after adult NSC divisions is still not known. This also holds
chloride channel-linked GABAA receptors (GABAA R) and G true for other features associated with the apical membrane,
protein-coupled GABAB receptors (GABAB R), and the loss of such as the cilium (and therefore SHH signaling) or with the
both types of receptors increases stem cell proliferation in the DG basal process, such as CcnD2 mRNA (Tsunekawa et al., 2012).
(Duveau et al., 2011; Song et al., 2012; Giachino et al., 2014a). A potential difference between the mechanisms underlying stem
GABA has well characterized roles in inhibiting proliferation cell divisions in the embryonic and adult brain is that during
and promoting differentiation of neuronal precursors during development, daughter cells that retain stem cell properties upon
embryonic development. In the adult DG, tonic (extra-synaptic) asymmetric division must also retain structures and molecules
GABA released from parvalbumin-positive interneurons, signals that promote proliferation, while the opposite might be true for
through GABAA R to maintain the quiescent state of adult adult NSCs, as their long-term maintenance depends on their
NSCs (Song et al., 2012). In the V-SVZ, GABAA signaling also ability to return to quiescence. In this respect, differences in the
suppresses stem cell proliferation via a mechanism involving reported preferred angle of division, vertical for embryonic radial
phosphorylation of the histone H2AX (Fernando et al., 2011). glia and horizontal for adult NSCs in the SGZ (Kempermann
Acetylcholine has been reported to have an opposite role to et al., 2004; Bonaguidi et al., 2011) might be significant. When
GABA and to promote the proliferation of NSCs in the adult a DG NSC divides in the adult brain, the basal daughter cell
hippocampus (Itou et al., 2011). Since physical exercise increases (prospective NSC) might inherit the basal radial process but
the release of acetylcholine in the hippocampus, this neurotrans- lose the apical membrane and its associated pro-proliferative
mitter may contribute to the stimulatory effect of exercise on signals, which would only persist in the apical daughter cell
adult neurogenesis (Suh et al., 2007; Mitsushima et al., 2009; Itou (prospective IPC) and contribute to its mitotic behavior. Further
et al., 2011). Other neurotransmitters can affect cell proliferation studies on the polarity of NSCs would greatly contribute to our

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Urbán and Guillemot Embryonic vs. adult hippocampal neurogenesis

Table 1 | Summary table of the effects during embryonic and adult hippocampal neurogenesis of the main pathways and transcription factors
discussed in the text.

Gene/pathway Effect during development Effect in adult neurogenesis Similar or different?

Wnt Promotes proliferation and neuronal differentiation Promotes activation of quiescent stem cells and Similar
of neural precursors enhances neuronal differentiation
BMPR-Ia Promotes the proliferation of neural precursors Maintains stem cells in a quiescent state Different
Notch Maintains the NSC pool by preventing premature Maintains the NSC pool by preventing exit from Similar
differentiation quiescence
Neurog2 Determines the glutamatergic differentiation of Expressed in glutamatergic neuronal precursors Similar?
NSCs but function not directly tested
Tbr2 Essential for the proliferation and differentiation of Essential for the proliferation and differentiation of Similar
IPCs IPCs
Prox1 Promotes differentiation and determines granule Expressed by granule neuron precursor cells, pro- Similar
cell identity motes differentiation
NFIX Required for correct positioning of NSCs in the Not analyzed (only straight knockout analyzed at ?
postnatal DG P20)
Tlx Does not have an important role in development of Essential for the proliferation of adult NSCs Different
the DG (although only straight knockout tested)
CcnD2 Does not have an important role in development of Essential for the proliferation of adult NSCs Different
the DG (although only straight knockout tested)
Ascl1 Does not have an important role in development of Essential for the proliferation of adult NSCs Different
the DG

understanding of the regulation of stem cell divisions in adult 2007; Gao et al., 2011). MicroRNAs also have major roles in
neurogenesis. the regulation of adult NSCs (Lopez-Ramirez and Nicoli, 2014).
The microRNA miR-124 promotes neuronal differentiation of
OTHER MECHANISMS THAT CONTROL NEUROGENESIS precursor cells of the V-SVZ lineage, partly through repression of
A great variety of additional intrinsic factors and signaling the stem cell factor Sox9 (Cheng et al., 2009). A good example of
molecules have been shown to regulate adult neurogenesis, but a microRNA with expression in both embryonic and adult neuro-
space is lacking to discuss here their function in any detail. genesis is the brain-enriched microRNA miR-9. miR-9 suppresses
Amongst them, the TF Sox1 is worth mentioning for its neu- the expression of key transcriptional regulators of NSCs during
rogenic function during development and its expression in a development, including Hes1, Tlx and REST (Packer et al., 2008;
subset of activated NSCs in the adult DG (Kan et al., 2007; Zhao et al., 2009; Bonev et al., 2012; Tan et al., 2012; Coolen
Venere et al., 2012). Pax6, expressed by radial glial cells in the et al., 2013). Although miR-9 expression has been detected in the
developing cerebral cortex, has essential and extensively studied adult neurogenic niches in mice, functional studies have not been
functions in embryonic neurogenesis (Heins et al., 2002). Pax6 performed yet (Deo et al., 2006; Kapsimali et al., 2007).
is also expressed by NSCs and IPCs in the V-SVZ and the SGZ, Cell cycle related proteins may also affect specific aspects
and it has a prominent role in adult olfactory neurogenesis, of adult stem cell behavior, as already discussed for CcnD2.
where it is required for the specification of subsets of olfactory Cyclin-dependent kinases inhibitors such as p21 and p27 in
bulb interneurons (Hevner et al., 2006; Brill et al., 2008). In the V-SVZ, and p27 and p57 in the SGZ play vital roles in the
neuroblasts from the V-SVZ, Pax6 recruits Brg1, a member of maintenance of adult NSC quiescence (Doetsch et al., 2002;
the Brg1/Brm associated factors (BAF) chromatin-remodeling Furutachi et al., 2013; Marqués-Torrejón et al., 2013; Andreu
complex. The interaction of Pax6 with the BAF complex is essen- et al., 2014). During embryonic neurogenesis, radial glial stem
tial for the pro-neurogenic effects of Pax6, and is in particular cells have short cell cycles, and the progression from proliferative
required to activate transcription of the neurogenic TF genes to differentiative divisions is associated with a lengthening of the
Sox11, Nfib and Pou3f4 (Ninkovic et al., 2013). However, the cell cycle, specifically of the G1 phase (Lange and Calegari, 2010).
role of Pax6 in hippocampal neurogenesis has not yet been Neural stem cells in the adult V-SVZ and SGZ have a shorter
studied. The transcriptional repressor REST/NRSF (repressor ele- cell cycle than early IPCs but this is due to a shorter S-phase
ment 1-silencing transcription/neuron-restrictive silencer factor) rather than to a shorter G1-phase (Brandt et al., 2012; Ponti et al.,
is highly expressed in stem cells and non-neuronal cell types 2013). Moreover, differentiating neuronal precursors also have a
of the embryo, where it represses the expression of neuronal- shorter cycle than early IPCs (Brandt et al., 2012), suggesting that
specific genes (Chong et al., 1995; Schoenherr and Anderson, the regulation of the cell cycle and the relationships between cell
1995; Ballas et al., 2005). In the adult DG, REST is expressed cycle dynamics and differentiation potential may differ between
by NSCs and mature granule cells and it is required to maintain embryonic and adult neurogenesis.
NSCs in a quiescent and undifferentiated state, at least in part Besides molecular signals known to operate during both
by direct repression of Ascl1 and NeuroD1 (Palm et al., 1998; developmental and adult neurogenesis, diverse stimuli generated
Calderone et al., 2003; Kuwabara et al., 2004; Jessberger et al., outside of the nervous system can also affect adult neurogenesis.

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Urbán and Guillemot Embryonic vs. adult hippocampal neurogenesis

FIGURE 3 | Niche regulation of mouse adult stem cells in the activation signals are interpreted by adult stem cells is still not known.
dentate gyrus. (A) Representation of a neural stem cell (blue) in the Here we show several intracellular factors that have been linked to
adult subgranular zone of the dentate gyrus and some of its the quiescent (left, Hes5, p. 57, FoxO3 and REST) or active (right, Tlx,
interactions with the niche. Granule neurons (yellow), interneurons Ascl1 and CcnD2) state of stem cells in the adult DG. We also show
(red), intermediate precursors (green) and astrocytes (purple) are other factors expressed in NSCs with no clear function in the switch
shown providing quiescence cues, while blood vessels and astrocytes from quiescence to activation (Sox2, Pax6, GFAP and GLAST) in the
are shown providing activation cues. (B) How quiescence and central part of the schematized cell.

The vasculature, for instance, is a crucial component of the adult divergences in the regulation and function of stem cells in the two
neurogenic niche (Shen et al., 2008; Tavazoie et al., 2008). A adult neurogenic niches (Figure 3).
great variety of endothelial-derived factors (Shen et al., 2004; Genetic analysis of adult neurogenesis suggests that it is an
Ramírez-Castillejo et al., 2006; Kokovay et al., 2010; Gómez- unstable process, since removal of individual regulatory genes
Gaviro et al., 2012; Pineda et al., 2013; Delgado et al., 2014) often results in dramatic changes in the behavior of adult stem
and recently cell-cell contact between endothelial cells and NSCs cells. This inherent instability might reflect the strong impact that
(Ottone et al., 2014) have been shown to modulate adult stem environmental cues have on stem cell activity. That defects in
cell behaviors, mostly in the context of V-SVZ neurogenesis. single quiescence pathways are sufficient to drive the cell cycle re-
Many other stimuli, some of which with no known function entry of subsets of stem cells also suggests that different pools of
in embryonic neurogenesis, such as hormones, inflammation, adult stem cells might receive and/or respond to different niche
ageing, or mental disorders are also amongst the many parameters signals. Further investigations will determine whether adult NSCs
affecting adult neurogenesis that fall beyond the scope of this in the DG are indeed heterogeneous and whether this is due
review (Seki and Arai, 1995; Kuhn et al., 1996; Shingo et al., 2003; to exposure to different niche signals or to intrinsic differences
Galea et al., 2006; Snyder et al., 2011; Kyritsis et al., 2012; Gebara between distinct NSCs.
et al., 2013; Schoenfeld and Cameron, 2014; Sierra et al., 2014;
Valero et al., 2014). ACKNOWLEDGMENTS
We are grateful to Jimena Andersen, Isabelle Blomfield and Iván
Crespo Enríquez for critical reading of this manuscript, and
CONCLUSIONS to Hayley Wood for graphic illustrations. We apologize to the
Adult neurogenic niches can be conceptualized as remnants of researchers whose work is not cited due to space limitations. Work
embryonic signaling centers (i.e., the septum/antihem giving rise in the laboratory of François Guillemot is supported by a Grant-
to the V-SVZ and the CH generating the SGZ): they are the source in-Aid from the Medical Research Council, UK (U117570528).
of instructive signals that determine the fate of neighboring stem
cells. However, in contrast with stem cells in the developing brain
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