Cellular and Molecular Attributes of Neural Stem Cell Niches in Adult Zebrafish Brain

Research Article Developmental Neurobiology
DOI 10.1002/dneu.22508
Cellular and Molecular attributes of Neural Stem Cell

Niches in Adult Zebrafish Brain.
Surendra Kumar Anand and Amal Chandra Mondal*
Cellular & Molecular Neurobiology Lab, School of Life Sciences, Jawaharlal

Nehru University, New Mehrauli Road, New Delhi, India. PIN-110067
e-mail: surend23_sls@jnu.ac.in
*Associate Professor in Cellular & Molecular Neurobiology, School of Life

Sciences, Jawaharlal Nehru University, New Mehrauli Road, New Delhi,
India. PIN-110067
Phone: +91-11-2670-4505 Fax: +91-11-2674-2558
e-mail: acmondal@mail.jnu.ac.in
This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record. Please cite this article as an
‘Accepted Article’, doi: 10.1002/dneu.22508
© 2017 Wiley Periodicals, Inc.
Received: Dec 30, 2016; Revised: Apr 05, 2017; Accepted: Jun 02, 2017
This article is protected by copyright. All rights reserved.

Developmental Neurobiology Page 2 of 33
ABSTRACT
Adult neurogenesis is a complex, presumably conserved phenomenon in vertebrates with a broad

range of variations regarding neuronal progenitor/stem cell niches, cellular composition of these
niches, migratory patterns of progenitors, etc. among different species. Current understanding of
the reasons underlying the inter-species differences in adult neurogenic potential, the
identification and characterization of various neural progenitors, characterization of the
permissive environment of neural stem cell niches and other important aspects of adult
neurogenesis is insufficient. In the last decade, zebrafish has emerged as a very useful model for
addressing these questions. In this review, we have discussed the present knowledge regarding
the neural stem cell niches in adult zebrafish brain as well as their cellular and molecular
attributes. We have also highlighted their similarities and differences with other vertebrate
species. In the end, we shed light on some of the known intrinsic and extrinsic factors that are
assumed to regulate the neurogenic process in adult zebrafish.
Keywords: adult neurogenesis; progenitors; stem cell niches; zebrafish
INTRODUCTION
For a long time, it was believed that the cells in the intact adult vertebrate brain do not exhibit
cell division (Altman, 1962). However, in the past few decades, several studies have reported
constitutively active neurogenesis and functional plasticity in the adult brain of a plethora of
vertebrate species (Goldman and Nottebohm, 1983; Lois and Alvarez-Buylla, 1994; Zupanc
and Horschke, 1995; Gould et al., 1999; Kornack and Rakic, 1999; Pencea et al., 2001; DeWulf
and Bottjer, 2005; Kroehne et al., 2011; März et al., 2011; Zupanc and Sîrbulescu, 2011;
Baumgart et al., 2012; Kishimoto et al., 2012; Kizil et al., 2012). Interestingly, there are marked
differences in the adult neurogenic capacity among different species (Tanaka and Ferretti, 2009;
Poss, 2010). The brains of adult mammals including humans exhibit very limited neurogenic
capacity. Also, the majority of the progenitors in the adult mammalian brain are lineage
restricted. Birds and reptiles show greater degrees of adult neurogenesis in comparison to
mammals. The most remarkable adult neurogenic capacity among vertebrates has been
documented in teleost fishes. Although, marked differences in the adult neurogenic capacity of
different vertebrate species is well established, the reasons behind these differences remain
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Page 3 of 33 Developmental Neurobiology
unexplained. At the same time, it is possible that growing knowledge about neurogenesis and
reparative regeneration in the adult brain may give way to novel therapeutic strategies to treat
neurological disorders involving loss of neurons and their associated brain function.
In the past decade, adult zebrafish brain owing to its remarkable neurogenic capacity has
emerged as a valuable model for the study of cellular and molecular attributes of neurogenesis
and reparative regeneration in the adult brain. It owns many features that are similar to those of
other vertebrate species, including humans, at many levels of biological organization (e.g., brain
anatomy, biochemical processes, neurochemistry, and amino acid sequence of proteins or
nucleotide sequence of genes) and is therefore considered a valuable tool not only for
fundamental research but for translational research as well (Miller and Gerlai, 2011). The robust
neurogenic capacity of adult zebrafish can be attributed to the numerous neural stem cell niches
present in its brain (Kizil et al., 2012; Lindsey et al., 2012). This is in contrast to the adult
mammalian brains which has a comparatively smaller proportion occupied by neural stem cell
niches and hence possess a limited potential for adult neurogenesis. These stem cell niches are
composed of a heterogeneous population of cells which altogether give rise to a permissive
environment for constitutive adult neurogenesis (Kizil et al., 2012). It would be befitting to ask
how these permissive micro-environments are different from the situation in other areas of the
brain where negligible or no proliferative activity has been documented. Also intriguing is the
fact that apart from the constitutively rapid cycling progenitors, adult zebrafish brain is also
composed of slow cycling quiescent stem cells (Kizil et al., 2012; Lindsey et al., 2012). These
quiescent neural stem cells may not actively participate in neurogenesis in the intact adult brain,
but in the case of injury or homeostatic imbalance, they show a remarkable increase in their
proliferation activity. Numerous studies have documented the functional and regulatory
attributes of adult neurogenesis in zebrafish (de Oliveira-Carlos et al., 2013; Diotel et al., 2013;
Edelmann et al., 2013; Berberoglu et al., 2014; Lenkowski and Raymond, 2014; Lindsey et al.,
2014; Lindsey and Tropepe, 2014; Diotel et al., 2015a; Diotel et al., 2015b; Rodriguez Viales et
al., 2015; Than-Trong and Bally-Cuif, 2015; Diotel et al., 2016). However, the majority of the
factors that orchestrate this unique process are still elusive. In this review, we have emphasized
the essential elements of our current understanding of the complex process of adult neurogenesis
in zebrafish. At places, we have compared the structural and functional organization of adult
neurogenic machinery in zebrafish with its counterpart in mammals and other vertebrates.

Finally, we discuss some of the riddles concerning adult neurogenesis that seek the attention of
investigators in this field.
NEUROGENIC ZONES IN ADULT ZEBRAFISH BRAIN
The new neurons in the adult zebrafish brain arise from stem/progenitor cells residing in
specialized areas in the brain (Adolf et al., 2006; Grandel et al., 2006). It is widely believed that
the cells within the adult stem/progenitor cell niches provide a specialized microenvironment that
harbors and regulates the activity of neuronal progenitors mainly through their interactions with
the surrounding cells (Kizil et al., 2012). Moreover, such progenitor zones are unique in terms of
their cellular composition and the molecular factors that maintain their plasticity (Lindsey et al.,
2012). In the mammalian and avian brain, the neural stem cell niches are mainly situated in the
telencephalon (Doetsch and Scharff, 2001; Alvarez-Buylla et al., 2002; Vellema et al., 2010).
Likewise in reptiles and amphibians, the neural stem cell niches are found mainly in the
telencephalon. However, some neurogenic activity has also been reported in diencephalon and
mesencephalon (Raucci et al., 2006; Berg et al., 2010; Kizil et al., 2012). In comparison to higher
vertebrates, a large number of neurogenic sites have been reported in teleost fishes located along
the rostrocaudal axis of the brain as well as in spinal cord (Zikopoulos et al., 2001; Zupanc et al.,
2005; Grandel et al., 2006; Ampatzis and Dermon, 2007; Kaslin et al., 2008; Zupanc, 2008)
which reflects the enormous capability of adult neurogenesis and brain regeneration in teleost
brain (Kroehne et al., 2011; März et al., 2011; Zupanc and Sîrbulescu, 2011; Baumgart et al.,
2012; Kishimoto et al., 2012; Kizil et al., 2012). Here we discuss the distinctive features of these
proliferation zones.
In the mammalian brain, the neuronal progenitors are mainly clustered in two sites within
telencephalon: the sub-ventricular zone (SVZ), also known as the sub-ependymal zone (SEZ), of
lateral ventricles in the forebrain and the sub-granular zone (SGZ) of dentate gyrus in the
hippocampus (Seri et al., 2001; Carleton et al., 2003; Kempermann et al., 2003; Seri et al., 2004).
In adult zebrafish brain, as many as sixteen different progenitor zones have been reported so far
(Grandel et al., 2006; Kizil et al., 2012). All of these progenitor zones are distributed along the
entire rostrocaudal axis of the brain. Major neurogenic sites in the adult zebrafish brain in which

neurogenic activity has been documented include primary sensory structures such as, olfactory
bulb, optic tectum, and higher order telencephalic regions as well as cerebellum (Lindsey and
Tropepe, 2014). The progenitor zones of telencephalon are the most studied neuronal
stem/progenitor cell niches in the adult zebrafish brain. The stem/progenitor cell populations
within the telencephalon are clustered around the ventricles in two distinct domains: the ventral
telencephalic progenitor domain (VTPD) and the dorsal telencephalic progenitor domain
(DTPD) (Adolf et al., 2006; Grandel et al., 2006; Kizil et al., 2012).
The VTPD is situated dorso-ventrally between the dorsal and ventral nuclei of ventral
telencephalon or subpallium (Kizil et al., 2012; Grandel and Brand, 2013). It runs longitudinally
from the olfactory bulb to the anterior commissure (Kizil et al., 2012). The DTPD lies along the
ventricular surface of the dorsal telencephalon or pallium (Kizil et al., 2012; Grandel and Brand,
2013). It harbors numerous clusters of proliferating cells that are dispersed throughout the entire
ventricular surface (Adolf et al., 2006; Grandel et al., 2006; Ganz et al., 2010). Both VTPD and
DTPD extend anteriorly to the caudal most part of the olfactory bulbs (Grandel and Brand,
2013). Dispersed proliferating cells have also been reported to reside in the olfactory bulbs (Byrd
and Brunjes, 2001; Ekström et al., 2001; Zupanc et al., 2005; Adolf et al., 2006; Grandel et al.,
2006; Kizil et al., 2012). Apart from these, in the optic tectum of adult zebrafish brain, a zone of
proliferating cells has been reported to be present in the posterior part, facing the tectal ventricle
(Grandel et al., 2006; Ito et al., 2010). Similar sort of proliferative zone has also been reported in
the optic tectum of goldfish and medaka (Raymond et al., 1983; Nguyen et al., 1999). The
cellular composition of different neurogenic zones and the unique features of the different cell
types residing within these zones are discussed in the next section.
CELLULAR COMPOSITION OF ADULT NEUROGENIC ZONES
The cellular composition of adult mammalian neurogenic regions has been extensively studied
and is considered as the basis of comparison as the neurogenic zones in other species are
described (Seri et al., 2004; Lindsey et al., 2012). In the SVZ of mouse, the presence of five
principal types of cells has been demonstrated: the glial fibrillary acidic protein (GFAP)
expressing neural stem cells (also known as type B1 cells); astroglia (or type B2cells); transient-
amplifying progenitor cells (or type C cells; these are presumably committed to a neuronal fate);
migrating neuroblasts (type A cells); and the ependymal cells lining the ventricles (type E cells)

(Lindsey et al., 2012). The first four cell types reside beneath the type E cells. Type B1 astroglia
have been demonstrated to be the resident adult neural stem cells in the SVZ (Doetsch et al.,
1999; Lindsey et al., 2012). This view has also been supported by evidence from studies using
transgenic mice expressing the thymidine kinase of herpes simplex virus under the control of
GFAP promoter. When these mice were exposed to anti-viral agent ganciclovir, it resulted in the
selective ablation of proliferating cells (Sofroniew and Vinters, 2010). Also, it has been
demonstrated that the astrocytic stem cells in the adult brain in rodents arise from the embryonic
radial glia-like stem cells (Merkle et al., 2004; Miyata et al., 2004; Noctor et al., 2004;
Fuentealba et al., 2015). Lineage-restricted astrocytic neural stem cells are also found in the
brain parenchyma, but they are quiescent in the intact adult brain and only undergo proliferation
following an insult or injury to the brain (Buffo et al., 2008; Burns et al., 2009; Kizil et al.,
2012). Moreover, the parenchymal astrocytic stem cells can be experimentally induced to
proliferate and act as neuronal progenitors in vitro as well as in vivo (Heinrich et al., 2010;
Kronenberg et al., 2010; Kizil et al., 2012).
The astrocytic stem cells in the SVZ generate the transit-amplifying cells which proliferate to
give rise to the neural precursors or neuroblasts. These neuroblasts take a long tangential
migratory route to the olfactory bulbs, where they differentiate into the interneurons (Kishimoto
et al., 2011). The stream of tangentially migrating cells is known as the "rostral migratory
stream" (RMS). In the rodent RMS, the migrating cells have been reported to move along each
other forming chains (Kishimoto et al., 2011). The astrocytes in the RMS form glial tubes, which
overlay the path for the migrating neuroblasts and direct them to the olfactory bulb (Jankovski
and Sotelo, 1996; Kishimoto et al., 2011). Apart from that, it has been reported that the cilia of
ependymal cells lining the surface of the ventricles beat in the direction of cerebrospinal fluid
flow and regulate the migration of the neural precursors (Guirao et al., 2010; Hirota et al., 2010;
Mirzadeh et al., 2010; Kishimoto et al., 2011). Recent studies have highlighted the potential role
of blood vessels as a scaffold for the migration of cells in the rodent RMS (Bovetti et al., 2007;
Saghatelyan, 2009; Snapyan et al., 2009; Whitman et al., 2009).
In the SGZ of mouse, the presence of four principal cell types has been demonstrated: the neural
stem cells (type 1 cells); an intermediate proliferative stage (type D1 cells); a committed
neuronal progenitor (type D2 cells); and immature granule interneurons (type D3 cells) (Seri et

al., 2004; Steiner et al., 2006; Lindsey et al., 2012). The type 1 neural stem cells have two
distinct subtypes: the radial cells and the horizontal cells (Suh et al., 2007). Both type 1 cells
generate the neuroblasts via the intermediate proliferative stage. The neuroblasts differentiate
over time to give rise to immature granule interneurons (Lindsey et al., 2012) that later on
migrate and incorporate into the granular cell layer (Kizil et al., 2012).
Needless to say, following a brain injury, the rate of proliferation of cells in these stem cell
niches is enhanced by several folds (Aguirre et al., 2010a; Kernie and Parent, 2010; Kizil et al.,
2012). However, the majority of the neurons arising from these stem cells do not survive to
integrate into the functional brain circuitry (Webber et al., 2007; Di Giovanni, 2009; Huebner
and Strittmatter, 2009; Vandenbosch et al., 2009). It has been suggested that for trophic support,
the cell types in SVZ and SGZ remain in proximity to the vasculature within their respective
proliferation zones (Tavazoie et al., 2008; Lindsey et al., 2012). Type B1 cells; in particular,
have been demonstrated to contact the centrally located blood vessels via cytoplasmic extensions
arising from their basal surface. Besides, type B cells have also been shown to maintain contact
with the ventricle via an apical process (Kizil et al., 2012). In fact, the clustered processes from
type B cells, together with the ependymal cells, give rise to a prominent pinwheel-like structure
at the ventricular surface (Mirzadeh et al., 2008; Kizil et al., 2012). In contrast to mammals, the
periventricular neurogenic zones of adult avian and reptilian brain are devoid of type C cells and
a continuous layer of ependymal cells (Font et al., 2001; Garcı́a-Verdugo et al., 2002; Lindsey et
al., 2012). There are few pieces of evidence for the existence of a rostral migratory stream in
birds (Rousselot and Nottebohm, 1995; Kishimoto et al., 2011), but no such evidence has been
reported in reptiles till date.
Not much is known about the cellular composition of neural stem cell niches in adult zebrafish.
Within the VTPD, the neurogenic stem cells, the label retaining cells and the slow cycling cells
are believed to be confined to the dorsal part of the domain, while the fast cycling proliferating
cells reside in the ventral part of the domain (Kizil et al., 2012). Studies involving pulse-chase
experiments using BrdU and IdU have reported migration of VTPD originated neurons to all the
major nuclei in the subpallium and the olfactory bulbs (Grandel et al., 2006; Kizil et al., 2012).
In a recent study, the cellular composition of six different neurogenic niches in the
periventricular zone (PVZ) of adult zebrafish brain, namely dorsal telencephalic area (D), medial

zone of dorsal telencephalon (Dm), lateral zone of dorsal telencephalon (Dl), ventral zone of
ventral telencephalon (Vv), dorsal zone of ventral telencephalon (Vd) and anterior part of
parvocellular pre-optic nucleus (Ppa), have been investigated and characterized, suggesting a
clear distinction between the cellular composition of pallial and sub-pallial neurogenic niches
(Lindsey et al., 2012). In this study, seven distinct cell types have been recognized across the
PVZ of adult zebrafish brain namely type 2a, type 2b, type 3, type 4a, type 4b, type 5 and
periventricular neurons. The peculiar characteristics of these cell types are summarized in Table
1. The frequency of these cell types has been shown to vary between different zones. Type 2a
cells are radial glia-like GS+ cells that presumably resemble the astrocytic stem cells in the SVZ
of adult rodent brain (discussed earlier). Type 2b and type 4b are multi-ciliated whereas type 2a,
type 3, type 4a and type 5 are non-ciliated. Type 2b and type 4b cells are exclusively present in
Ppa. Combinely, in D, Vd, Dm, Dl and dorsal zone of Ppa, type 2a cells, along with neurons are
most abundant, while type 3, type 4a and type 5 cells are lesser in number. On the other hand, the
Vv and ventral zone of Ppa, are comprised of mainly the type 3 and type 4a cells, along with
neurons (Lindsey et al., 2012). Another significant finding of this study was that in comparison
to adult rodent brain, the ependymal cells were very less in all of the brain areas studied. The
ependymal cells were restricted to the roof of telencephalic ventricles and parts of the pallial
niches of D and Dm (Lindsey et al., 2012).
In the telencephalic proliferation zones, the neural stem cells generate neuroblasts that undergo
radial dispersion in the surrounding brain tissue where they give rise to differentiated HuC/D+
neurons (Grandel and Brand, 2013). The newborn neurons also express position specific markers
{e.g. subpallium: Pax6a, pallium: PVA; (Grandel and Brand, 2013)} and markers indicating
synapse formation (SV2) (Adolf et al., 2006; Grandel et al., 2006; Kroehne et al., 2011;
Rothenaigner et al., 2011) suggesting functional integration of these neurons in the brain tissue
(Grandel and Brand, 2013). Within the telencephalon, the pallium and subpallium are clearly
distinct from each other regarding their cell composition and expression of cell-specific gene
markers (Grandel and Brand, 2013). The pallial proliferative zone or DTPD is composed of both
dividing and non-dividing cells that are diffusely scattered across the ventricular surface of the
pallium (Adolf et al., 2006; Grandel et al., 2006; Ganz et al., 2010). Both glial cell-specific
marker positive and negative cells are present in the DTPD (Ganz et al., 2010; Marz et al., 2010).
Majority of the dividing cells in the DTPD express glial cell-specific markers such as GFAP,

vimentin (Vim), glutamine synthase (GS), S100β and Aromatase-B (Lam et al., 2009; Ganz et
al., 2010; Marz et al., 2010; Kizil et al., 2012). The non-glial proliferating cells in the DTPD
represent one-third of the total population of dividing cells (Grandel and Brand, 2013). The cells
expressing the glial cell-specific gene markers are presumably radial glia-like stem cells, as is
evidenced by their radial appearance with long processes arising radially from their cell body
(Grandel and Brand, 2013). These cells contact the vasculature in the pial surface via a long
process stemming from their basal end. The cells that do not express glial cell-specific markers
are believed to be differentiating neuroblasts (Kaslin et al., 2008; Chapouton et al., 2010; Ganz et
al., 2010; Marz et al., 2010). It can also be the case that they represent an entirely different class
of cells. In contrast to VTPD, newly differentiated neurons are integrated into the functional
circuitry of the brain tissue in a laminar fashion (Grandel et al., 2006). There are very few studies
that report the type of neurons arising from the neuronal progenitors in the DTPD. One such
study reported the presence of parvalbumin in these neurons (Grandel et al., 2006; Kizil et al.,
2012). Others reported the expression of pallial region-specific transcription factors in and
around DTPD (Berberoglu et al., 2009; Kizil et al., 2012). However, in the light of current
knowledge and because of the absence of firm evidence supporting the claims on the identity of
different proliferating and differentiating cell types, characterization of the cellular composition
of the neuronal stem cell niches in adult zebrafish brain remains elusive.
The situation in the subpallial neurogenic zone or VTPD in adult zebrafish brain is entirely
different from the pallial neurogenic zone. Here, the glial cell-specific gene marker expressing
cells constitute only a small fraction of the total population of proliferating cells in comparison to
pallium, where they are present in the vast majority of the total dividing population of cells
(Grandel and Brand, 2013). Rather, the majority of the proliferating cells in the subpallial
neurogenic zones express nestin, similar to the rodent SVZ (Adolf et al., 2006; Kaslin et al.,
2008; Ganz et al., 2010; Marz et al., 2010). It has been demonstrated that nestin-expressing
proliferating progenitors cells in the subpallial neurogenic zone resemble the neuro-epithelial
like progenitors of the mammalian SVZ (Ganz et al., 2010). Just like the radial glia-like
progenitors of the DTPD, the neuroepithelial-like progenitors in the VTPD also contact the
vasculature in the pial surface via an extended basally originating process (Grandel and Brand,
2013). However, none of the proliferating cell types present in the periventricular zone of an
adult zebrafish brain is known to have cell processes extending into the ventricular lumen

(Grandel and Brand, 2013). One of the reason for the inter-domain diversity in the cell
composition within the periventricular neurogenic niches could be the differential expression of
transcription factors (Ganz et al., 2010).
In the proliferation zone facing the tectal ventricle in the caudal part of optic tectum, new
neurons arising from the progenitors are added to the periventricular grey area (PGZ) in a
concentric manner, and this results in the growth of optic tectum (Ito et al., 2010). The
progenitors in this region differentiate into either GABA-ergic or glutamatergic neurons as well
as some other neurons expressing HuC marker (Grandel et al., 2006; Ito et al., 2010). Some of
them may also give rise to oligodendrocytes and radial glia (Ito et al., 2010). These progenitors
express neuroepithelial stem cell-like features and progenitor cell associated markers such as
Sox2 and Musashi1 (Ito et al., 2010). In the olfactory bulbs in adult zebrafish brain, studies
involving pulse-chase experiments using BrdU have demonstrated that within four weeks, the
number of BrdU+ cells is enhanced in the olfactory bulb by about six-fold (Byrd and Brunjes,
2001). It is appealing to note that within the specified time, the native cells can only undergo two
to three cell cycles. Hence, a significant number of progenitors must be active within the
olfactory bulbs. However, the possibility of proliferating cells from pallial and subpallial
neurogenic niches migrating to the olfactory bulbs cannot be ruled out (Grandel and Brand,
2013). The support for the migratory hypotheses comes from the fact that proliferating cells in
both pallial and sub pallial neurogenic niches express gene markers associated with migrating
cells such as PSA-NCAM (Adolf et al., 2006; Grandel et al., 2006; Kaslin et al., 2008;
Kishimoto et al., 2011). Most recently, the direct observation of migration of neural progenitors
of telencephalic origin to the olfactory bulb in adult zebrafish brain has been reported (Kishimoto
et al., 2011). During their migration, these cells take a route that is believed to be equivalent to
RMS in mammals. The cell first moves along the medial surface of the olfactory bulb and later
on settle in the lateral regions (Kishimoto et al., 2011). However, there are marked differences
between the adult mammalian RMS and the telencephalon to olfactory bulb migratory route
observed in adult zebrafish. For instance, the migrating progenitors in zebrafish are not
surrounded by a glial tube that is a peculiar feature of RMS in the adult mammalian brain
(Kishimoto et al., 2011). This suggests that in contrast to rodent RMS, the movement of
differentiating neuroblasts in zebrafish is independent of a glial tube. In such a situation, the
vasculature along the migratory route presumably serves as the primary scaffold for the

migrating progenitors (Kishimoto et al., 2011). Hence an RMS-like functional migratory route
exists in the adult zebrafish brain. However, the current evidence is still insufficient to support
the existence of a duly organized and functional RMS in zebrafish.
FACTORS REGULATING NEUROGENESIS IN ADULT ZEBRAFISH

BRAIN
Given the complexity of the structural and functional organization of the neurogenic machinery,
many cellular and molecular mechanisms are believed to be involved in orchestrating the unique
process of adult neurogenesis. There are numerous puzzles regarding the regulation of adult
neurogenesis which, when solved, has the potential to give way to new strategies to treat
neurodegenerative diseases. However, despite a plethora of reports from numerous studies, the
knowledge of the regulatory mechanisms underlying adult neurogenesis is still incomplete. In the
following section, we have discussed some of the regulatory factors that are known to affect
neurogenesis.
Growth Factors: Growth factors are well known for their function to regulate and maintain the
stem cell activity in a variety of species (Krampert et al., 2010; Mira et al., 2010; Prajerova et al.,
2010; Kizil et al., 2012). However, in zebrafish, reports regarding their function are inadequate.
Therefore, we have discussed a few of the growth factors and their role in the context of adult
neurogenesis in zebrafish.
Fibroblast growth factor (FGF): It is one of the well characterized mitogenic growth factor in
vertebrates (Wills et al., 2008). It is presumably one of the major signals promoting proliferation
of neuronal progenitors in parts of telencephalon and cerebellum (Kaslin et al., 2009; Ganz et al.,
2010; Kizil et al., 2012). In the cerebellum of adult zebrafish brain, fgfr2 and fgfr3 are known to
mediate Fgf signaling (Kizil et al., 2012). fgf3, fgf8a, and fgf8b are expressed in cerebellum of
adult zebrafish brain (Kaslin et al., 2009; Kizil et al., 2012). FGF signaling has also been shown
to regulate the proliferation of progenitors in telencephalic neuronal stem cell niches (Ganz et al.,
2010; Kizil et al., 2012). Blocking of FGF signaling decrease proliferation, while over-
expression of FGF promote proliferation in distinct telencephalic progenitor niches (Ganz et al.,

2010; Kizil et al., 2012). All these reports indicate that FGF signaling may be intricately linked
to progenitor cell proliferation in adult zebrafish telencephalon. Hence, further investigation in
this regard is a fascinating field of research.
Brain derived neurotrophic factor (BDNF): It is a protein belonging to neurotrophin family. In

mammals, BDNF promotes neuronal growth, differentiation and survival via tropomyosin-
related receptor kinase B (TrkB) receptors (Huang and Reichardt, 2001). In addition, it has been
shown to modulate neuronal migration and myelination (Cosgaya et al., 2002; Carter et al.,
2003). The function of BDNF in the regulation of developmental neurogenesis is well
characterized as a promoter of neuronal differentiation and survival (Lindholm et al., 1996).
However, the potential role of BDNF in adult neurogenesis remains uncharted. In zebrafish, a
recent report suggests that BDNF is abundantly expressed in several regions of the forebrain
(Cacialli et al., 2016). Interestingly, BDNF was observed to be expressed by neurons and not by
radial glia or progenitor cells in adult zebrafish brain (Cacialli et al., 2016). Further investigation
is needed to elaborate the neurogenic and regenerative function of BDNF in adult zebrafish
brain.
Apart from these, other growth factors such as pigment epithelium-derived growth factor
(PEDGF) and glial cell-derived neurotrophic factor (GDNF) have also been implicated in
regulating the stem cell activity in adult zebrafish brain (Chen et al., 2005; Kobayashi et al.,
2006; Ramirez-Castillejo et al., 2006; Wei et al., 2007; Kizil et al., 2012). However, their exact
neurogenic and regenerative role in adult zebrafish brain still awaits exploration.
Notch signaling: Notch signaling has been shown to be essential for maintenance and self-
renewal of neural stem cells in rodents (Yoon et al., 2004; Ables et al., 2010; Aguirre et al.,
2010b; Ehm et al., 2010; Imayoshi et al., 2010). The role of Notch signaling during embryonic
neurogenesis has been thoroughly studied (Wang et al., 2001; Geling et al., 2004; Scholpp et al.,
2009). However, its role in controlling adult and reparative neurogenesis remains largely
uncharted. Notch receptors are known to negatively regulate the differentiation of neurons and
oligodendrocytes and positively regulate the formation of astroglia (Gaiano et al., 2000; Tanigaki
et al., 2001; Genoud et al., 2002; Park and Appel, 2003; Givogri et al., 2006; Louvi and
Artavanis-Tsakonas, 2006; Schebesta and Serluca, 2009). Besides, during embryogenesis, Notch
signaling is known to play a pivotal role in the fate determination of neural progenitors (Park and

Appel, 2003; Shin et al., 2007; Tallafuss et al., 2009). Notch 1 receptor is expressed by a number
of cell types in distinct mammalian brain regions including astrocytes in SVZ, migratory
neuroblasts in ependymal layer, a subset of cells in the olfactory bulbs, in sub-granule cells of the
dentate gyrus, and in Purkinje cells of the cerebellum (Stump et al., 2002; Givogri et al., 2006;
Breunig et al., 2007; Ehm et al., 2010; Imayoshi et al., 2010; Lugert et al., 2010). The primary
Notch receptors found in the zebrafish genome are notch1a, notch1b, notch2 and notch3
(Bierkamp and Campos-Ortega, 1993; Westin and Lardelli, 1997). These genes are expressed by
different types of cells present in the telencephalon of adult zebrafish brain (Chapouton et al.,
2010). The recent analysis proposed that except for notch 2, all the other receptor types are found
in almost all the neurogenic regions of adult zebrafish brain and are expressed by the major
fraction of proliferating cell population (de Oliveira-Carlos et al., 2013). In the dorsal
telencephalon of adult zebrafish brain, inhibition of Notch signaling leads to an enhanced
proliferation of neuronal progenitors whereas over-expression of the constitutively active
intracellular domain of Notch receptor results in reduced progenitor proliferation (Chapouton et
al., 2010; Kizil et al., 2012). This suggests a role of Notch signaling in upholding the neural stem
cells in the quiescent state (Chapouton et al., 2010; Kizil et al., 2012). Further examination is
required to elaborate the precise effect of Notch signaling on neurogenic activity in the adult
zebrafish brain.
Bmp signaling: Bmp presumably plays an inhibitory role in adult neurogenesis in mammals
(Mira et al., 2010; Kizil et al., 2012). In fact, neurogenesis cannot take place until Bmp is
antagonized by noggin expression (Bonaguidi et al., 2008; Mira et al., 2010; Kizil et al., 2012).
In zebrafish, Bmp signaling is known to modulate the behavior of neural precursors during
embryonic development (Jia et al., 2009). However, its role in adult neurogenesis in zebrafish
remains unexplored. In a study employing ectopic expression of bmp2b gene in zebrafish, it was
seen that the proliferation of progenitors in telencephalon was decreased (Kizil et al., 2012). This
is indicative of an inhibitory role of Bmp signaling on adult neurogenesis in zebrafish, as in
mammals. Further examination and detailed mapping of Bmp expression and activity in adult
zebrafish brain are needed for elaborating the influence of Bmp on neurogenesis in the adult
zebrafish brain.

Wnt signaling: In mammals, Wnt signaling is recognized for its role in developmental
neurogenesis (Galceran et al., 2000; Lee et al., 2000; Zhou et al., 2004). It presumably affects
proliferation, migration and differentiation of neuronal progenitors during embryonic
development (Lie et al., 2005; Machon et al., 2007; Wexler et al., 2009; Qu et al., 2010; Zhang et
al., 2010a). During post-natal neurogenesis, some studies suggest that Wnt signaling keeps
neural progenitors from differentiating (Machon et al., 2007; Mutch et al., 2010). Others,
involving ectopic Wnt expression, propose that Wnt signaling can both act as an activator or an
inhibitor of neuronal differentiation depending on the context (Kuwabara et al., 2009; Imura et
al., 2010; Tang et al., 2010). Together, these evidence point towards a model in which Wnt
signaling promotes neurogenesis in the initial stage but has to be inhibited in later stages for
differentiation to proceed (Wang et al., 2012). High levels of Wnt signaling have been observed
in the hypothalamus of adult zebrafish brain (Wang et al., 2009; Kizil et al., 2012). It has also
been shown that Wnt signaling is required for neurogenesis in zebrafish hypothalamus during
embryonic development (Lee et al., 2006; Kizil et al., 2012). Recently, it was demonstrated that
as in mammals, Wnt signaling is first necessary for proliferation and expansion of unspecified
progenitors in the embryo and later, in post-embryonic stages, control the differentiation of
GABA-ergic and serotonergic lineages (Wang et al., 2012). Further, it was seen that inhibition of
Wnt signaling is necessary for neuronal differentiation, but does not seem to affect
differentiation of radial glia (Wang et al., 2012). So far, there are no clear reports about the
cellular targets of Wnt signaling in the adult zebrafish brain. In adult mouse brain, Wnt activity
has been shown to be present in ventricular and parenchymal cells of the mediobasal
hypothalamus that also express neural progenitor cell-specific markers (Wang et al., 2012). But
in adult zebrafish brain, the identity of cells expressing Wnt activity needs to be clarified. Also,
the role of Wnt signaling in neurogenesis outside the hypothalamus needs thorough
investigation.
Cytokines and Chemokines: The cytokines are secreted by immune cells in the brain such as
microglia, and are recognized to play diverse roles in cell proliferation and survival (Molina-
Holgado and Molina-Holgado, 2010; Kizil et al., 2012). Tumor necrosis factor (TNF) is an
important cytokine that presumably has an inhibitory effect on neurogenesis in hippocampus of
adult zebrafish brain (Gonzalez-Perez et al., 2010; Kizil et al., 2012). However, the biological

significance of cytokines in neurogenesis and regeneration in adult zebrafish brain still needs to
be established.
One of the essential characteristics of adult neurogenesis and brain regeneration is the migration
or movement of progenitors or differentiating neurons from the site of origin to their functional
destination in the neural circuitry. However, our understanding of the signals that guide these
cells to their destination is limited. Chemokines are small signaling molecules that mediate the
chemotactic movement of their target cells. In the adult mammalian brain, chemokines are
expressed by a variety of cells and mediate the interaction between neurons and other cell types
(Cartier et al., 2005; de Haas et al., 2007; Kizil et al., 2012). In zebrafish, the chemokine Cxcll2
and its receptor Cxcr4 have been found to be necessary for a number of processes including
lateral line migration, germ cell guidance, muscle formation, and development of forebrain and
retina (David et al., 2002; Doitsidou et al., 2002; Knaut et al., 2003; Gilmour et al., 2004; Li et
al., 2005; Chong et al., 2007; Palevitch et al., 2010; Kizil et al., 2012). It has been reported that
Cxcr4 and Cxcll2 are expressed by radial glia in the telencephalon of adult zebrafish brain
(Diotel et al., 2010; Kizil et al., 2012). However, the detailed expression profile is lacking.
Further, the role of other chemokines and chemokine receptors has not been addressed. Hence,
the study of cytokines and chemokines in the context of adult neurogenesis in zebrafish
represents an interesting research realm.
Sexual dimorphism in neural stem cell activity: In birds and mammals, it has been reported
that sex-specific differences in adult neurogenic potential exist. Birds in particular show
progenitor activity in neuronal vocal circuits in forebrain intimately linked to male courtship
behavior and song production (Hidalgo et al., 1995; Nordeen et al., 1998; Katz et al., 2008). In
mammals, the SGZ region in the hippocampal dentate gyrus exhibits sex-specific differences in
progenitor activity with males having reduced numbers of newly born neurons in comparison to
females (Zhang et al., 2008; Kim and Casaccia-Bonnefil, 2009). Sex-specific proliferation
patterns have also been reported in the SVZ region of the adult mammalian brain (Peretto et al.,
2001; Díaz et al., 2011). Similar sort of sex-specific regulation of neurogenic activity has also
been reported in teleost fishes (Zikopoulos et al., 2001; Ampatzis and Dermon, 2007). In a recent
study employing short-term survival experiments, it was demonstrated that the central part of the
dorsal telencephalic area, the ventral part of the periventricular pretectal nucleus, and the

periventricular nucleus of posterior tuberculum had enhanced numbers of proliferating cells in

female zebrafish than in males (Ampatzis et al., 2012). Also the dorsal zone of the
periventricular hypothalamus in male zebrafish exhibit higher density of actively proliferating
cells than in females (Ampatzis et al., 2012). Moreover, the sexual dimorphism in the neurogenic
ability suggests that the sex-related patterns of neurogenic activity might have been a conserved
feature in the course of evolution.
The sexual dimorphism in neurogenic capacity may stem from the differential influence of sex-
specific steroidal hormones on neuroendocrine functions (McCarthy, 2009; Balthazart et al.,
2010; Lenz et al., 2012). In fact, several studies have reported the effect of sex steroids on the
maintenance and regulation of neuroendocrine and behavioral circuitry. However, in recent
years, there is an enhancing interest in the study of the influence of these sex steroids on
neurogenesis (Brinton et al., 2008; McCarthy, 2009). In the next segment, we give a brief
account of the effect of two major sex steroids, progesterone, and estrogen, on the behavior of
neuronal progenitors.
Progesterone: In mammals, the existence of two isoforms of nuclear progesterone receptor,

PRA, and PRB, has been reported (Gronemeyer et al., 1987). Recently, progesterone membrane
receptors have also been characterized in mammals (Thomas, 2008; Labombarda et al., 2010). In
the rodent brain, both the embryonic and adult brain has several sites in the hypothalamic and
extra-hypothalamic regions that express nuclear or membrane receptors for progesterone (Diotel
et al., 2011). In vivo studies in the adult mice have reported that following ischemic brain stress,
progesterone increases the survival and migration of newborn neurons in dentate gyrus and SVZ
of the hippocampus (Zhang et al., 2010b; Zhang et al., 2010a). During specific periods in
embryonic brain development in rodents, PRA and PRB are expressed in several regions in the
forebrain (Quadros et al., 2007; Lopez and Wagner, 2009) suggesting the potential role of
progesterone signaling in brain development. However, there has rarely been any study
addressing the involvement of progesterone on neurogenesis in teleost fishes. Some studies have
suggested the existence of a functionally active progesterone synthetic pathway in the adult
zebrafish brain (Sakamoto et al., 2001; Diotel et al., 2011). Besides, a novel nuclear progesterone
receptor named pgr has been identified and characterized in the zebrafish brain. It has been
experimentally established that progestins including progesterone binds to and activate the pgr

receptor (Chen et al., 2010). Initially, it was reported that pgr is widely distributed in zebrafish
brain (Hanna et al., 2010). Recently, more detailed information about the distribution of this
receptor in the brain has been documented (Diotel et al., 2011). It was reported that progesterone
targets are distributed in many parts of the brain, particularly in the preoptic area and
hypothalamus. Also, it was demonstrated that radial glial cells stain more strongly for pgr
compared to neurons indicating that progesterone may directly influence their behavior. In the
same study, it was also reported that similar to mammals, estrogens can cause up-regulation of
Pgr in the brain of zebrafish (Diotel et al., 2011). All these evidences indicate that progesterone
might be able to modulate neural stem cell behavior and therefore may be a key player in adult
neurogenesis. However, the consolidation of these hypotheses demands deeper investigation.
Estrogen: Estrogen is known to be an important regulatory factor in embryonic neurogenesis

(Lephart, 1996). However, whether or not it plays equally important role in adult neurogenesis
remains undefined. Previous studies have reported a multifaceted role of estrogen in cell
proliferation. Short-term exposure to estradiol is known to enhance cell proliferation in the adult
brain hippocampus of mammalian females (Ormerod et al., 2003; Barha et al., 2009). On the
other hand, long-term estradiol treatment decreases granule cell proliferation in the dentate gyrus
of the adult female mammalian hippocampus (Ormerod et al., 2003). Interestingly, long-term
estradiol exposure in adult mammalian males increases proliferation in the dentate gyrus (Saravia
et al., 2007). Furthermore, the short-term estradiol treatment in adult female rodents decreases
cell proliferation in SVZ (Brock et al., 2010) and also leads to a decline in the cell density of
newborn neurons in the olfactory bulbs (Hoyk et al., 2006; Brock et al., 2010). This suggests a
general trend in estrogen's influence on neural stem cell activity. Despite a raft of reports in
mammals, the effect of estrogen on neural stem cell activity in adult zebrafish has not been
studied so extensively and hence is a widely open area for research. Estrogen synthesis requires
an enzyme complex that involves aromatase B (aroB) (Simpson and Davis, 2001), which is also
a cell-specific marker for radial glial progenitors. In fact, intense aroB activity is a prominent
feature of adult zebrafish brain (Forlano et al., 2001; Menuet et al., 2005; Strobl-Mazzulla et al.,
2008) and the expression of aroB is associated with neuronal stem cell niches (Pellegrini et al.,
2007; Diotel et al., 2011). In a recent study, it was reported that manipulation of the estrogenic
environment in the neuronal stem cell niches in adult zebrafish brain leads to altered neuronal
progenitor behavior (Diotel et al., 2013). Estrogen was shown to inhibit neurogenic activity

(Diotel et al., 2013). In another study, it was reported that estrogen alters the proliferation pattern
in the adult zebrafish brain in a region-specific manner (Makantasi and Dermon, 2014). These
pieces of evidence, taken together, advocate a major role of estrogen in modulating neurogenic
activity in the adult zebrafish brain. However, further exploration is needed to strengthen this
theory.
Age: It is a well-established fact that the activity of neural stem cells in the post-natal brain
progressively declines with increasing age (Maslov et al., 2004; Molofsky et al., 2006; Rao et al.,
2006; Nishino et al., 2008; Knoth et al., 2010; Lugert et al., 2010; Encinas et al., 2011; Sanai et
al., 2011). However, the reasons for the age-related decline of neurogenic capacity are yet to be
described. We do not even know for sure whether it is a universal phenomenon or is
characteristic of selected species. In a recent study, it was demonstrated that zebrafish shows
noticeable signs of aging (Kishi et al., 2009). More recently, it has been reported that zebrafish
also exhibits an age-related decline in neurogenic potential and that this decrease can be
attributed to changes in the cycling behavior of the neural stem cells and not to the reduction in
their number (Edelmann et al., 2013).
CONCLUSION
The marked differences in the neurogenic potential among different vertebrate species are
intriguing, and the underlying causes for these inter-species differences are still elusive. Part of it
can be attributed to the differences in number and composition of the sites of neurogenesis in the
adult brain - the neuronal stem cell niches. Numerous studies have attempted to characterize
these stem cell niches in terms of their cellular composition and the permissive environment that
is not found in surrounding non-neurogenic brain tissue. However, the present level of
knowledge relating to the identity of cells present in neuronal stem cell niches, the cycling
behavior of these cells, various intrinsic and extrinsic factors regulating and maintaining
neuronal stem cell activity, patterning and differentiation cues, etc. is insufficient and
incomplete. Adult zebrafish brain serves as an excellent model to examine these aspects. Its ease
of handling and maintenance, proper techniques enabling experimental manipulation and
sufficient homology with humans at many levels of biological organization makes it a favorite
and preferred model for exploring the realm of adult neurogenesis and reparative regeneration. In
the current review, we discussed the recent and past knowledge regarding the ultra-structural

organization of neuronal stem cell niches in the adult zebrafish brain. We also highlighted some
of the similarities and differences between zebrafish and other vertebrates regarding adult
neurogenesis. This knowledge is useful to help understand the basic features of adult
neurogenesis in zebrafish and may provide a base for further investigations leading to new
findings in this splendid model organism.
Acknowledgements: We highly acknowledge the grants supported by UPE-II (Project Id No.

247) (UGC), DST PURSE-II, UGC RN, UGC DRS SAP and DBT NER
(BT/PR16164/NER/95/88/2015) (Govt. of India) to ACM.
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Legends for Figures and Tables
Figure 1: Location and cellular composition of neuronal stem cell niches in adult rodent and
zebrafish brain.
a and b. Parasagittal sections of adult mouse and zebrafish brain highlighting the different
proliferation zones (shown in blue) and adult neural stem cell (aNSC) niches (shown in yellow).
c and d. Schematic representation of the cellular organization of aNSC niches in the SVZ (c) and
SGZ(d) of adult mouse brain.
e and f. Schematic representation of cellular organization of aNSC niches in the sub-pallium (e)
and pallium (f) of adult zebrafish brain.
g and h. Different types of cells present in the proliferation zones of adult mouse (g) and adult
zebrafish (h) brain.
Figure 2: Schematic model of the influence of signaling molecules and growth factors on adult
neurogenesis in zebrafish.
Table 1. Characteristics of morphologically distinct cell types found in the periventricular

proliferation zones in adult zebrafish brain (Classification given by Lindsey et al., 2012).

Figure 1: Location and cellular composition of neuronal stem cell niches in adult rodent and zebrafish brain.
a and b. Parasagittal sections of adult mouse and zebrafish brain highlighting the different proliferation
zones (shown in blue) and adult neural stem cell (aNSC) niches (shown in yellow).
c and d. Schematic representation of the cellular organization of aNSC niches in the SVZ (c) and SGZ(d) of
adult mouse brain.
e and f. Schematic representation of cellular organization of aNSC niches in the sub-pallium (e) and pallium
(f) of adult zebrafish brain.
g and h. Different types of cells present in the proliferation zones of adult mouse (g) and adult zebrafish (h)
brain.
118x157mm (300 x 300 DPI)

Figure 2: Schematic model of the influence of signaling molecules and growth factors on adult neurogenesis
in zebrafish.
102x117mm (300 x 300 DPI)

Table 1. Characteristics of morphologically distinct cell types found in the periventricular zone
in adult zebrafish brain (Classification given by Lindsey et al., 2012).
Periventricular
Type 2a Type 2b Type 3 Type 4a Type 4b Type 5
Neurons
Frequency Frequent Infrequent Frequent Frequent Infrequent Infrequent Frequent
Multi- Non-
Cilia Non-ciliated Multi-ciliated Non-ciliated Non-ciliated --xx--
ciliated ciliated
Subpopulation
BrdU+, Subpopulation Subpopulation
subpopulation Subpopulation BrdU+, BrdU+, No labeling No labeling
Labelling HuC/D+
GS+, S100β+ subpopulation subpopulation detected detected
subpopulation S100β+ S100β+
S100β+


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Research Article Developmental Neurobiology

Cellular and Molecular attributes of Neural Stem Cell

Surendra Kumar Anand and Amal Chandra Mondal*

Cellular & Molecular Neurobiology Lab, School of Life Sciences, Jawaharlal

*Associate Professor in Cellular & Molecular Neurobiology, School of Life

Phone: +91-11-2670-4505 Fax: +91-11-2674-2558

This article is protected by copyright. All rights reserved.

Adult neurogenesis is a complex, presumably conserved phenomenon in vertebrates with a broad

Keywords: adult neurogenesis; progenitors; stem cell niches; zebrafish

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NEUROGENIC ZONES IN ADULT ZEBRAFISH BRAIN

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CELLULAR COMPOSITION OF ADULT NEUROGENIC ZONES

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FACTORS REGULATING NEUROGENESIS IN ADULT ZEBRAFISH

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Brain derived neurotrophic factor (BDNF): It is a protein belonging to neurotrophin family. In

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periventricular nucleus of posterior tuberculum had enhanced numbers of proliferating cells in

Progesterone: In mammals, the existence of two isoforms of nuclear progesterone receptor,

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Estrogen: Estrogen is known to be an important regulatory factor in embryonic neurogenesis

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Acknowledgements: We highly acknowledge the grants supported by UPE-II (Project Id No.

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Legends for Figures and Tables

Table 1. Characteristics of morphologically distinct cell types found in the periventricular

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118x157mm (300 x 300 DPI)

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102x117mm (300 x 300 DPI)

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Frequency Frequent Infrequent Frequent Frequent Infrequent Infrequent Frequent

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