Biochem. J. (2013) 450, e1–e2 (Printed in Great Britain)
e1
doi:10.1042/BJ20130176
COMMENTARY
How Sox2 maintains neural stem cell identity
Gerald THIEL1
Department of Medical Biochemistry and Molecular Biology, University of Saarland Medical Center, D-66421 Homburg, Germany
The transcription factor Sox2 [SRY (sex-determining region Y)box 2] is expressed at the earliest developmental stages in the
nervous system and functions as a marker protein for neural
development. Sox2 is found in embryonic neural stem cells as
well as in virtually all adult neural stem cells of the subventricular
region and the subgranular zone of the hippocampus. Gain-offunction and loss-of-function experiments in transgenic animals
revealed a key role for Sox2 in the maintenance of neural stem
cell properties, including proliferation/survival, self-renewal and
neurogenesis. A limited set of Sox2-responsive target genes have
been identified, including the genes encoding the neural stem cell
marker nestin and the signalling molecule sonic hedgehog. In this
issue of the Biochemical Journal, Feng et al. identified the survivin
gene as a target for Sox2 in neural stem cells. Survivin protects
cells from programmed cell death and functions as a regulator
of cell division. The regulation of survivin expression by Sox2
explains why the reduction of the Sox2 concentration in neural
stem cells is accompanied by a reduced proliferation of the cells
and an induction of apoptosis. It would be of interest to know
whether the Sox2–survivin connection is a common scheme to
maintain the ‘stemness’ identity of other stem/progenitor cells.
Sox [SRY (sex determining region Y)-box] 2 belongs to the Sox
family of transcription factors that are characterized by the
presence of the HMG (high-mobility group) box originally found
in the testis-determining SRY protein. There are 20 Sox proteins
expressed in mammals. The Sox proteins bind through their HMG
DNA-binding domains with comparable activities. On the basis
of the primary structure of their HMG domain, Sox proteins
are divided into subfamilies. Sox2 together with Sox1 and Sox3
comprise the B-subgroup of the Sox family of transcription factors
on the basis of their highly homologous HMG domains.
The Sox proteins are expressed in many tissues during
development. High expression of Sox-encoding genes is found
in the developing nervous system; here, Sox2 functions as a
marker for neural development as it is already expressed in
undifferentiated precursor cells. Furthermore, Sox2 is expressed
in embryonic and adult neural stem cells, where expression
persists until the cells differentiate. Accordingly, reprogramming
of neural stem cells to pluripotent stem cells does not require
the additional expression of Sox2. In the adult, Sox2 is highly
expressed in the stem cells of the neurogenic regions of
the subventricular zone and in the subgranular layer of the
hippocampal dentate gyrus. These stem cells, which express
the stem cell marker nestin and the glial marker GFAP (glial
fibrillary acidic protein), are characterized by their capability for
self-renewal and their potency in the generation of neurons and
glia cells. Sox2 also marks bona fide adult stem and progenitor
cells outside of the nervous system, including stem cells of the
stomach, cervix, anus, testes, lens and multiple glands [1]. Thus
Sox2 is unique in showing expression in embryonic stem cells,
fetal progenitor cells and adult stem cells.
The functions of Sox2 in neural stem cell biology have been
investigated using several transgenic animal models. Gain-offunction experiments have revealed that forced expression of
Sox2, or its paralogues Sox1 or Sox3, maintains the properties and
characteristics of stem cells and prevents neuronal development
[2].
Inactivation of the Sox2-encoding genes in transgenic
mice causes early embryonic lethality. Thus loss-of-function
experiments have been performed with genetically altered mice
leading to hypomorphic or conditional/knockout mutations [3].
Conditional inactivation of Sox2 in the mouse embryonic brain
induced a complete loss of nestin/GFAP-positive neural stem
cells. In addition, cell proliferation of neural stem cells decreased,
whereas apoptotic markers increased [4]. The loss of Sox2
interfered with the development of the hippocampus, leading to
an almost complete loss of the dentate gyrus at P7. The loss of
neural stem cells occurred in the subventricular zone at much
lower levels, suggesting that neural stem cells from the dentate
gyrus and the subventricular zone have different sensitivities
to Sox2 [4]. A hypopmorph with only 25–30 % expression of
Sox2 in the brain showed a significant impairment of neural stem
cell proliferation and neurogenesis in the neurogenic regions.
The number of nestin/GFAP-expressing neural stem cells was
significantly reduced. The reduction in neural progenitors and the
proliferation defect resulted in the generation of fewer neurons
from these stem cells [5]. These results highlight a key function
of Sox2 in the maintenance of neural stem cells.
To understand how Sox2 maintains neural stem cells in their
progenitor state, target genes of Sox2 have to be identified that
encode proteins required to conserve the ‘stemness’ identity of
neural stem cells. It will be particularly intriguing to determine
whether there is a group of Sox2-responsive genes that regulates
the ‘stemness’ identity of these stem/progenitor cells. Only a
limited number of Sox2-responsive genes in neural stem cells have
been identified so far. Together with POU [Pit-1 (pituitary-specific
positive transcription factor 1)/octamer/Unc-86] transcription
factors, Sox regulates the nestin gene in neural primordial cells
[6]. Nestin expression in neural stem cells is important for
Key words: apoptosis, neural stem cell, neurogenesis, SRY
(sex-determining region Y)-box 2 (Sox2), survivin.
Abbreviations used: GFAP, glial fibrillary acidic protein; HMG, high-mobility group; IAP, inhibitor of apoptosis; Shh, sonic hedgehog; SRY, sex-determining
region Y; Sox, SRY box.
1
email gerald.thiel@uks.eu
c The Authors Journal compilation c 2013 Biochemical Society
e2
G. Thiel
guaranteeing a proper self-renewal of neural stem cells [7]. Sox2
binds to the gene encoding Shh (sonic hedgehog) in neural stem
cells. Shh is required for the normal growth of neural stem cells
in vitro and functions as a potent mitogen for neural progenitor
cells in the brain. Loss of Sox2 is accompanied by a loss of Shh
in the hippocampal primordium. This Sox2–Shh connection was
corroborated by pharmacological and genetic rescue experiments
in vivo and in vitro [4], suggesting that reduced Shh activity is,
at least in part, responsible for the hippocampal neural stem cell
defects in Sox2-deficient mice.
In this issue of the Biochemical Journal, Feng et al. [8] present
data showing that Sox2 activates expression of the survivin gene
in neural stem cells. Survivin, a member of the IAP (inhibitor
of apoptosis) family of proteins, prevents programmed cell death
via co-operative interaction with XIAP (X-linked IAP), another
IAP protein. In addition, survivin functions as a regulator of cell
division. Accordingly, conditional deletion of survivin results in
mitotic defects and cell death [9]. Feng et al. [8] showed that
overexpression of Sox2 increased survivin expression, whereas
knockdown of Sox2 led to decreased survivin concentration in
the cells and an induction of programmed cell death. Furthermore,
forced expression of survivin protected neural stem cells from the
programmed cell death normally induced by the knockdown of
Sox2. These data were corroborated in vivo by in utero injection
of Sox2-specific small hairpin RNA in the presence or
absence of a survivin expression vector into the lateral ventricle
of the mouse brain at E14.5 (embryonic day 14.5). The
results provide an explanation for the observation that in Sox2
hypomorphic mice reduced levels of Sox2 result in proliferation
defects and an up-regulation of apoptosis in neural stem cells.
Thus the up-regulation of survivin expression by Sox2 contributes
to the maintenance of the ‘stemness’ identity of neural stem cells
by supporting the survival of the cells. In concert with other Sox2
target genes, such as the genes encoding nestin or Shh as well as
other not yet identified genes, the identity of neural stem cells is
preserved.
Sox2 regulates important functions not only in neural stem
cells of the CNS (central nervous system), but also in a variety of
other tissue-specific stem/progenitor cells [1]. It will be important
to elucidate whether Sox2 regulates a common set of genes in
these cells to promote the self-renewal potential and to inhibit
apoptosis or differentiation. However, the fact that Sox2 function
is dose- and context-dependent argues for a stem cell-type specific
set of Sox2 target genes that maintain the properties of these
cells. This is illustrated by the observations that Sox2 plays a key
role in the regulation of the Notch pathway in retinal progenitor
cells, whereas only marginal effects on the Notch pathway were
observed in the hippocampal neural stem cells expressing reduced
Received 1 February 2013; accepted 4 February 2013
Published on the Internet 28 February 2013, doi:10.1042/BJ20130176
c The Authors Journal compilation c 2013 Biochemical Society
levels of Sox2 [4,10]. Thus Sox target genes may differ depending
upon the stem cell type and the period of development. In addition,
the chromatin architecture of Sox2 target genes may be different
in various tissue-specific stem/progenitor cells. The expression
of the survivin gene has recently been shown to depend on the
activity of chromatin-modifying proteins such as Bmi1 (BMI1
polycomb ring finger oncogene), a component of the polycomb
repressive complex 1 [11]. These results highlight the necessity
of analysing both the expression of Sox2 target genes in different
types of stem cells and the chromatin structure of these target
genes. Sox2 will stay in the limelight and the sum of Sox2 target
genes will certainly explain the ‘stemness’ character in molecular
terms.
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