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Ryoichiro Kageyama · Tetsuo Yamamori
Editors
Cortical
Development
Neural Diversity and Neocortical
Organization
Cortical Development
Ryoichiro Kageyama • Tetsuo Yamamori
Editors
Cortical Development
Neural Diversity and Neocortical
Organization
Editors
Ryoichiro Kageyama Tetsuo Yamamori
Kyoto University National Institute for Basic Biology
Kyoto, Japan Okazaki, Japan
ISBN 978-4-431-54495-1 ISBN 978-4-431-54496-8 (eBook)

DOI 10.1007/978-4-431-54496-8
Springer Tokyo Heidelberg New York Dordrecht London
Library of Congress Control Number: 2013945765
© Springer Japan 2013

This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of
the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation,
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Springer is part of Springer Science+Business Media (www.springer.com)

Preface
Development of the cerebral cortex, the center for higher brain functions such as
cognition, memory, and decision making, is one of the major targets of current
research. This book reviews recent progress in cortical development research,
focusing on the mechanisms of neural stem cell regulation, neuronal diversity and
connectivity formation, and neocortical organization. The cerebral cortex is
divided into many areas, including motor, sensory, and visual cortices, each of
which consists of six layers containing a variety of neurons with different activities
and connections. Such diversity of neuronal types and connections is generated at
various levels. First, the competency of neural stem cells changes over time, giving
sequential rise to distinct types of neurons and glial cells: initially deep layer neu-
rons, then superficial layer neurons, and lastly astrocytes. The activities and con-
nections of neurons are further modulated via interactions with other brain regions,
such as the thalamocortical circuit, and via input from the environment. Extensive
studies are gradually elucidating the mechanisms by which the diversity in such
neuronal types and connections is formed. To accelerate exchanges of the most
recent findings and interactions among leading researchers, we organized a sympo-
sium titled “Cortical Development” in Okazaki, Japan, held March 10–13, 2012,
which was supported by a Grant-in-Aid for Scientific Research on the Innovative
Area “Neural Diversity and Neocortical Organization” from the Ministry of
Education, Culture, Sports, Science and Technology (MEXT) of Japan. The sym-
posium was very timely and attracted many young researchers, who were eager to
interact with leading researchers and learn about the most recent hot topics.
Because the symposium was so successful, we decided to publish a book on corti-
cal development and asked the researchers in this field to contribute chapters. We
were happy that many of them responded positively and, although they were very
busy, contributed chapters that review hot topics in this field. Many of the topics
discussed in the symposium are included in this book.
v
vi Preface
We are pleased to be able to publish this book, and we would like to thank all the
authors who contributed state-of-the-art reviews to it. We also thank our editorial
partners, Mr. Kaoru Hashimoto and Ms. Mari Hata at Springer Japan, for their ini-
tial suggestion and continued promotion of the project.
Ryoichiro Kageyama
Tetsuo Yamamori
Contents
1 Dynamic Notch Signaling in Neural Progenitor Cells ......................... 1

Hiromi Shimojo, Yuki Maeda, Toshiyuki Ohtsuka,
and Ryoichiro Kageyama
2 Proneural Proteins and the Development of the
Cerebral Cortex....................................................................................... 19
Julian Heng and François Guillemot
3 The Role of the Transcription Factor Pax6 in Brain
Development and Evolution: Evidence and Hypothesis ...................... 43
Noriko Osumi and Takako Kikkawa
4 Regulatory Mechanisms Underlying the
Neurogenesis-to-Gliogenesis Switch by Neural Stem Cells ................. 63
Takuya Shimazaki
5 Specification of GABAergic Neocortical Interneurons ........................ 89
Goichi Miyoshi, Robert P. Machold, and Gord Fishell
6 Regulation of Cortical Circuit Formation ............................................ 127
Fernanda M. Rodríguez-Tornos, Beatriz Cubelos,
and Marta Nieto
7 Neocortical Neurogenesis and Circuit Assembly ................................. 153
Peng Gao, Khadeejah T. Sultan, Xin-Jun Zhang,
and Song-Hai Shi
8 Hierarchical Organization of Neocortical Neuron Types.................... 181
Yasuo Kawaguchi
9 Emerging Roles of Heparan Sulfate in Axon
Guidance Signaling ................................................................................. 203
Masayuki Masu
vii
viii Contents
10 The Roles of RECK, a Membrane-Anchored Regulator

of Pericellular Proteolysis, in Neural Development ............................. 215
Makoto Noda
11 Synapse Formation in the Brain ............................................................ 229
Masayoshi Mishina, Tomoyuki Yoshida, Misato Yasumura,
and Takeshi Uemura
12 Genomic Imprinting in the Mammalian Brain .................................... 249
Wei-Chao Huang and Christopher Gregg
13 Genes Selectively Expressed in the Visual Cortex
of the Old World Monkey....................................................................... 263
Yusuke Komatsu, Shigeko Toita, Masanari Ohtsuka,
Toru Takahata, Shiro Tochitani, and Tetsuo Yamamori
Index ................................................................................................................. 277

Chapter 1
Dynamic Notch Signaling in Neural
Progenitor Cells
Hiromi Shimojo, Yuki Maeda, Toshiyuki Ohtsuka, and Ryoichiro Kageyama
Abstract Notch signaling plays an essential role in maintenance of neural

progenitor cells. Differentiating neurons express Notch ligands such as Delta-like1
(Dll1), which activate Notch signaling in neighboring cells. Activation of Notch
signaling induces the expression of Hes1 and Hes5, which repress proneural gene
expression, thereby maintaining neural progenitor cells. Thus, differentiating neurons
keep their neighbors undifferentiated. Interestingly, Hes1 expression oscillates with
a period of 2–3 h by negative feedback, and Hes1 oscillations drive the oscillatory
expression of Dll1 and the proneural gene Neurogenin2 (Neurog2). Neurog2 oscil-
lation cannot induce neuronal differentiation, and Dll1 oscillation leads to the
mutual activation of Notch signaling between neighboring cells. Thus, neural pro-
genitor cells also keep each other undifferentiated via oscillation in Notch signaling.
Not all cells express Hes1 in an oscillatory manner: cells in boundary regions such
H. Shimojo • R. Kageyama (*)

Institute for Virus Research, Kyoto University, Shogoin-Kawahara, Sakyo-ku,
Kyoto 606-8507, Japan
Japan Science and Technology Agency, CREST, Shogoin-Kawahara, Sakyo-ku,
World Premier International Research Initiative–Institute for Integrated Cell-Material
Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8501, Japan
e-mail: [email protected]
Y. Maeda
Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan
T. Ohtsuka
Japan Science and Technology Agency, CREST, Shogoin-Kawahara, Sakyo-ku,
R. Kageyama and T. Yamamori (eds.), Cortical Development: Neural Diversity 1

and Neocortical Organization, DOI 10.1007/978-4-431-54496-8_1, © Springer Japan 2013
2 H. Shimojo et al.
as the isthmus express Hes1 in a sustained manner, and this sustained Hes1 expres-
sion seems to be important for the maintenance of boundary regions. Thus, Notch
signaling molecules regulate various aspects of neural development by changing the
expression dynamics.
Keywords Basal progenitor • Neuroepithelial cell • Oscillatory expression • OSVZ

progenitor • Proneural gene • Radial glia
1.1 Introduction
Neuroepithelial cells, which extend from the ventricular surface to the pial surface
of the neural tube, repeat symmetric cell division, where each neuroepithelial cell
divides into two neuroepithelial cells (Fig. 1.1) (Alvarez-Buylla et al. 2001; Fishell
and Kriegstein 2003; Fujita 2003; Götz and Huttner 2005; Miller and Gauthier
2007). As the wall of the neural tube becomes thicker, neuroepithelial cells gradu-
ally elongate and become radial glial cells, which have cell bodies in the ventricular
zone and radial fibers reaching the pial surface (Fig. 1.1). Radial glial cells undergo
asymmetric cell division, where each radial glial cell divides into two distinct cell
types, a radial glial cell and an immature neuron or a progenitor (Fig. 1.1) (Malatesta
et al. 2000; Miyata et al. 2001; Noctor et al. 2001). Immature neurons migrate
Fig. 1.1 Neural progenitor cells and their differentiation in the embryonic brain. Initially, neuro-
epithelial cells undergo self-renewal by symmetric division and expand. As development proceeds,
neuroepithelial cells elongate to become radial glial cells, which have cell bodies in the inner
region (the ventricular zone) of the neural tube and radial fibers that reach the pial surface. Radial
glial cells give rise to neurons or basal progenitors. After the production of neurons, some radial
glial cells give rise to oligodendrocytes and ependymal cells. Radial glial cells finally differentiate
into astrocytes. Both neuroepithelial cells and radial glial cells are considered embryonic neural
progenitor cells
1 Dynamic Notch Signaling 3
outside of the ventricular zone along radial fibers into the cortical plate, where these
cells become mature neurons. Progenitors migrate out of the ventricular zone into the
subventricular zone (SVZ), proliferate further, and give rise to more neurons, which
then migrate into the cortical plate (see Fig. 1.6). Radial glial cells give rise to different
types of neurons, initially deep layer neurons and then superficial layer neurons, by
repeating asymmetric cell division (Fig. 1.1). Radial glial cells also give rise to oligo-
dendrocytes and ependymal cells and finally differentiate into astrocytes (Fig. 1.1).
Both neuroepithelial and radial glial cells are considered neural progenitor cells.
As described above, neural progenitor cells produce a variety of cell types
sequentially during development by gradually changing their competency over
time. Thus, it is very important to maintain neural progenitor cells until the final
point of development in order to generate the proper number of cells and the full
diversity of cell types. It has been shown that Notch signaling plays an essential role
in the maintenance of neural progenitor cells (Kopan and Ilagan 2009; Fortini 2009;
Pierfelice et al. 2011). Here, we review the recent progress on the mechanism and
role of Notch signaling in neural development.
1.2 The Core Pathway of Notch Signaling
Notch signaling plays an important role in cell proliferation and differentiation by

communication between neighboring cells. Notch ligands such as the transmembrane
proteins Delta-like1 (Dll1) and Jagged1 activate Notch receptors such as the trans-
membrane protein Notch1 in neighboring cells. Notch is cleaved at the S1 site by
Furin into two fragments that remain associated to form the functional heterodimer
receptor consisting of the Notch extracellular domain and the transmembrane part
(Fig. 1.2). Upon Notch ligand binding, Notch receptors undergo successive cleavages:
the transmembrane part of Notch proteins is cleaved at the S2 site by TACE and then
at the S3 site by γ-secretase, releasing the Notch intracellular domain (NICD) from
the transmembrane domain (Fig. 1.2). NICD next moves to the nucleus and forms a
complex with the DNA-binding protein Rbpj and the transcriptional co-activator
Maml (Fig. 1.2). This ternary complex (NICD-Rbpj-Maml) activates target genes
such as the basic helix-loop-helix (bHLH) repressor genes Hes1 and Hes5, mamma-
lian homologues of Drosophila hairy and Enhancer of split (Jarriault et al. 1995;
Fortini 2009; Honjo 1996; Kageyama et al. 2008; Kopan and Ilagan 2009; Pierfelice
et al. 2011). Hes factors act as repressors by interacting with the corepressor TLE/Grg,
a homologue of Drosophila Groucho, through the C-terminal Trp-Arg-Pro-Trp
sequence called the WRPW domain (Akazawa et al. 1992; Sasai et al. 1992; Grbavec
and Stifani 1996). Groucho is known to modify the chromatin structure by recruiting
the histone deacetylase Rpd3 (Chen et al. 1999). Hes1 and Hes5 repress the proneural
genes such as the bHLH transcriptional activators Ascl1 and Neurogenin2 (Neurog2),
which induce neuronal differentiation (Bertrand et al. 2002; Ross et al. 2003). As a
result, Hes1 and Hes5 inhibit neuronal differentiation and maintain neural progenitor
cells (Ishibashi et al. 1994; Ohtsuka et al. 1999; Hatakeyama et al. 2004; Kageyama
4 H. Shimojo et al.
Fig. 1.2 The core pathway of Notch signaling. Proneural genes such as Ascl1 (also called Mash1)
and Neurog2 (Ngn2) promote neuronal differentiation and induce the expression of Dll1, which in
turn activates Notch signaling in neighboring cells. Notch is cleaved at the S1 site by Furin into two
fragments that remain associated to form the functional heterodimer receptor consisting of the
Notch extracellular domain and the transmembrane part. Upon activation of Notch, the Notch
intracellular domain (NICD) is released from the transmembrane domain and transferred to the
nucleus, where it forms a complex with the DNA-binding protein Rbpj and the transcriptional
co-activator Maml. The NICD-Rbpj-Maml ternary complex induces the expression of transcrip-
tional repressor genes such as Hes1 and Hes5. Hes1 and Hes5 repress the expression of proneural
genes and Dll1, thereby leading to the maintenance of neural progenitor cells
et al. 2007). Hes genes also repress the expression of Notch ligand genes. Notch
ligand expression is induced by proneural genes, and therefore neurons
express Notch ligands and inhibit neighboring cells to differentiate into neurons by
activating Notch signaling. This process, called lateral inhibition, is essential to main-
tain neural progenitor cells in the developing nervous system. In the absence of Notch
signaling, all cells express proneural genes and initiate neuronal differentiation, result-
ing in premature depletion of neural progenitor cells without generating later-born cell
types (Ishibashi et al. 1995; Hatakeyama et al. 2004; Imayoshi et al. 2010).
While the Notch signaling pathway is important for maintenance of neural progeni-
tor cells, this regulation also suggests that neurons expressing Notch ligands are
required to activate the Notch pathway, raising the question as to how neural progenitor
cells are maintained during early stages of development before neurons are born.
1.3 Oscillatory Expression of Notch Signaling Genes
In the developing mouse dorsal telencephalon, neural progenitor cells express the
proneural gene Neurog2, the Notch ligand gene Dll1, and Hes1 in a salt-and-pepper
pattern at early stages before neurons are born. It is likely that Neurog2 induces the
Fig. 1.3 Oscillatory expression of Hes1 by negative feedback. Hes1 expression oscillates with a
period of ~2–3 h in many cell types such as neural progenitor cells and fibroblasts. Hes1 represses
its own expression by directly binding to its promoter. This negative feedback leads to the disap-
pearance of Hes1 mRNA and protein, because they are extremely unstable, allowing the next
round of its expression. In this way, Hes1 autonomously starts oscillatory expression
expression of Dll1, which upregulates Hes1 expression in neighboring cells,

suggesting that Notch signaling is active before neurons are born. This observation
raises another question: why neurons are not formed during early stages, although
the proneural gene Neurog2 is expressed.
It was previously shown that Hes1 expression oscillates with a period of about
2–3 h in many cell types (Hirata et al. 2002). This oscillatory expression is regulated
by negative feedback with a delayed timing (Fig. 1.3 ) (Hirata et al. 2002 ).
6 H. Shimojo et al.
Fig. 1.4 Expression dynamics of Hes1, Neurog2 (Ngn2), and Dll1 in neural progenitor cells and
differentiating neurons. Hes1 expression oscillates with a period of ~2–3 h in neural progenitor
cells. In these cells, Hes1 oscillation drives the oscillatory expression of Neurog2 and Dll1 by
periodic repression. It is likely that Neurog2 cannot induce neuronal differentiation when the
expression is oscillatory because many of its downstream genes do not respond to Neurog2 oscil-
lation. In contrast, when Hes1 expression disappears, Neurog2 expression becomes sustained, pro-
moting neuronal differentiation. Thus, the oscillatory versus sustained expression dynamics of
Neurog2 may be important for the choice between neural progenitor cells and neurons
Hes1 represses its own expression by directly binding to multiple N box sequences
(CACNAG) of its promoter (Takebayashi et al. 1994). Once the promoter is
repressed, Hes1 mRNA and protein disappear rapidly because they are extremely
unstable, and the disappearance of Hes1 protein allows the next round of its expres-
sion. In this way, Hes1 expression autonomously oscillates with a period of ~2–3 h
(Hirata et al. 2002). Because this oscillation is unstable and nonsynchronous, Hes1
expression levels are variable between neighboring cells, suggesting that a salt-
and-pepper pattern of Hes1 expression is due to unstable and non-synchronous
oscillation. Indeed, time-lapse imaging analysis revealed that Hes1 expression
oscillates in neural progenitor cells (Fig. 1.4) (Masamizu et al. 2006; Shimojo et al.
2008). Hes1 expression exhibits an inverse correlation with Neurog2 protein and
Dll1 mRNA expression in neural progenitor cells, suggesting that Hes1 oscillation
induces the oscillatory expression of Neurog2 and Dll1 by periodic repression
(Shimojo et al. 2008). Time-lapse imaging analysis revealed that Neurog2 and Dll1
expression also oscillates in neural progenitor cells, where Hes1 expression oscil-
lates (Fig. 1.4) (Shimojo et al. 2008). However, in differentiating neurons, where
Hes1 expression disappears, Neurog2 and Dll1 expression becomes sustained
(Fig. 1.4) (Shimojo et al. 2008). It is likely that Neurog2 cannot induce neuronal
differentiation when its expression oscillates, probably because many of its down-
stream genes do not respond to Neurog2 oscillation, and that Neurog2 induces neu-
ronal differentiation only when its expression becomes sustained. When Neurog2
expression oscillates, only rapidly responding genes such as Dll1 may be selectively
induced, and Dll1 oscillations may lead to the mutual activation of Notch signaling
and the maintenance of neural progenitor cells. Indeed, it was recently demonstrated
that Neurog2 is phosphorylated by cyclin-dependent kinases in neural progenitor
Fig. 1.5 Maintenance of neural progenitor cells by the mutual activation of Notch signaling. When
Hes1 expression is low in a subset of cells (Cell 1 in the upper panel), Neurog2 (Ngn2) and Dll1
expression becomes high, leading to the activation of Notch signaling and the upregulation of Hes1 in
neighboring cells (Cell 2 in the upper panel). In the latter cells, high levels of Hes1 repress Neurog2
and Dll1 expression, but due to oscillations, Hes1 expression becomes low after ~1 h, while Neurog2
and Dll1 expression becomes high (Cell 2 in the lower panel), leading to the activation of Notch sig-
naling in the former cells (Cell 1 in the lower panel). In this way, Dll1 oscillations lead to the mutual
activation of Notch signaling between neural progenitor cells without the aid of neurons
cells and that phosphorylated Neurog2 can induce Dll1 expression efficiently but
not other gene expression (Ali et al. 2011; Hindley et al. 2012). These results sug-
gest that Neurog2 may lead to two opposite outcomes, depending on its expression
dynamics: when its expression oscillates, Neurog2 induces the maintenance of neu-
ral progenitor cells, but when its expression is sustained, Neurog2 induces neuronal
differentiation.
These observations suggest that salt-and-pepper patterns of Neurog2, Dll1, and
Hes1 expression during early stages of development are the result of oscillatory
expression. It is generally thought that Neurog2- or Dll1-positive cells are selected
to become neurons first, while negative cells remain neural progenitor cells.
However, time-lapse imaging analyses indicated that positive cells could become
negative, while negative cells could become positive a few hours later, suggesting
that positive and negative cells may be equivalent to each other. We speculate that
Neurog2 and Dll1 oscillations enable the maintenance of neural progenitor cells by
activation of Notch signaling without the aid of neurons. When Hes1 expression is
low in a subset of cells (Cell 1 in the upper panel of Fig. 1.5), Neurog2 and Dll1
8 H. Shimojo et al.
expression becomes high, leading to the activation of Notch signaling and the
upregulation of Hes1 in neighboring cells (Cell 2 in the upper panel of Fig. 1.5).
In the latter cells, high levels of Hes1 repress Neurog2 and Dll1 expression, but due
to oscillations, Hes1 expression becomes low after ~1 h, while Neurog2 and Dll1
expression becomes high (Cell 2 in the lower panel of Fig. 1.5), leading to the acti-
vation of Notch signaling in the former cells (Cell 1 in the lower panel of Fig. 1.5).
In this way, Dll1 oscillations lead to the mutual activation of Notch signaling
between neural progenitor cells (Shimojo et al. 2008). Thus, oscillatory expression
is advantageous for maintaining a group of cells undifferentiated without any input
from neurons. In agreement with this notion, when sustained Hes1 expression is
induced in neural progenitor cells, their neighboring cells prematurely initiate neu-
ronal differentiation (Shimojo et al. 2008). This is probably because sustained
Hes1 expression represses Neurog2 and Dll1 expression continuously, resulting in
inactivation of Notch signaling in the neighboring cells. These observations also
suggest that Notch signaling is not a one-way mechanism (neuron to neural pro-
genitor cell), but functions by reciprocal transmission (neural progenitor cell to
neural progenitor cell).
At later stages of development, many differentiating neurons express Dll1 in a
sustained manner and activate Notch signaling in neural progenitor cells. Thus,
Neurog2 and Dll1 expression mostly occurs in neurons but not in neural progenitor
cells, although Hes1 expression in neural progenitor cells oscillates even at later
stages (Shimojo et al. 2008).
1.4 The Mechanism of Oscillatory Expression:

Lessons from the Segmentation Clock
The negative feedback loop is important but not sufficient for oscillatory expres-
sion. Both the instability of gene products and negative feedback with delayed tim-
ing are required for sustained oscillations, which was initially predicted by
mathematical modeling (Lewis 2003; Monk 2003; Jensen et al. 2003; Kageyama
et al. 2012). The detailed mechanism for oscillatory expression has been analyzed
in the somite segmentation clock. Somites are transient metameric structures, which
later give rise to the vertebral column, ribs, skeletal muscles, and subcutaneous tis-
sues. A bilateral pair of somites is formed by segmentation of the anterior parts of
the presomitic mesoderm (PSM), which is located in the caudal part of embryos.
In mouse embryos, each pair of somites is formed every 2 h, and this process is
controlled by Hes7, a member of Hes gene family (Bessho et al. 2001). Like Hes1,
Hes7 is expressed in an oscillatory manner in the PSM. Both loss of expression and
sustained expression of Hes7 lead to severe somite fusion, suggesting that oscillatory
expression of Hes7 is important for periodic somite segmentation. Hes7 oscillations
drive cyclic expression of many downstream genes such as genes in Notch signaling
and Fgf signaling (Bessho et al. 2001; Niwa et al. 2007, 2011). Hes7 oscillation is
also regulated by negative feedback: Hes7 protein directly binds to its own promoter
and represses its expression (Bessho et al. 2003).
Hes7 protein is very unstable: the half-life is only ~22 min, and further analyses
revealed that this instability is very important for Hes7 oscillations. Introduction of a
K14R point mutation (the 14th lysine residue is mutated to arginine) stabilizes Hes7
protein (the half-life is ~30 min) without changing the transcriptional repressor activity.
This mutation was found to dampen the Hes7 oscillation rapidly in mouse embryos,
resulting in steady (non-oscillatory) Hes7 expression and disorganized somite seg-
mentation after a few normal cycles, which agreed well with the prediction by math-
ematical modeling (Hirata et al. 2004). Another feature required for sustained Hes7
oscillation is the intronic delays, which include transcription and splicing of intron
sequences. Hes7 gene has three introns, and intronic delays for Hes7 expression were
found to be about 19 min (Takashima et al. 2011). It was shown that Hes7 oscilla-
tions were abolished by deletion of all three introns, as predicted by mathematical
modeling, indicating that intronic delays are essential for Hes7 oscillation (Takashima
et al. 2011). Removal of two introns shortens the intronic delays by about 5 min, and
according to the mathematical modeling, this shortened delays would dampen but
accelerate the oscillation. Indeed, deletion of two introns accelerates Hes7 oscillation
and somite segmentation, increasing the number of somites and vertebrae in the
cervical and upper thoracic region (Harima et al. 2013).
Hes1 protein is also very unstable (about ~20 min half-life), and the gene has
three introns. Thus, point mutations that change the stability of Hes1 protein and
deletions of introns would affect the dynamics of Hes1 oscillations, as observed
with Hes7 oscillations. It would be interesting to see what effects on neural progeni-
tors are caused by such mutations in the Hes1 gene.
1.5 Basal Progenitors and Outer Subventricular Zone

(OSVZ) Progenitors
As stated above, radial glial cells not only generate neurons but also produce
progenitors, which migrate into the subventricular zone (SVZ). There are two types
of progenitors, basal progenitors and outer SVZ (OSVZ) progenitors. Basal pro-
genitors formed by Tbr2 migrate into the SVZ, retract their apical and basal pro-
cesses, and generally divide only once to generate two neurons (Sessa et al. 2008).
Thus, basal progenitors have a limited proliferation ability. In these cells, Hes1 and
Hes5 expression is downregulated, suggesting that Notch signaling is not active
(Fig. 1.6) (Mizutani et al. 2007; Kawaguchi et al. 2008). By contrast, OSVZ pro-
genitors divide multiple times in the OSVZ and generate a large number of neurons
(Hansen et al. 2010; Fietz et al. 2010). These cells have radial glia-like morphology
extending radial fibers to the pial surface but lack apical processes and therefore are
not in contact with the ventricular surface (Fig. 1.6). OSVZ progenitors undergo
asymmetric cell division, where each cell divides into a daughter cell that inherits
10 H. Shimojo et al.
Fig. 1.6 Basal progenitors and OSVZ progenitors. Basal progenitors retract apical and basal
processes and generally divide only once to generate two neurons. In these cells, Hes1 expression
is downregulated, suggesting that Notch signaling is not active. OSVZ progenitors have radial glia-
like morphology extending radial fibers to the pial surface but lack apical processes. These cells
repeatedly undergo asymmetric cell division, each dividing into a daughter cell that inherits the
radial fiber (OSVZ progenitor) and the other that does not (neuron). Neurons express Notch ligands
and activate Notch signaling in their sibling OSVZ progenitors
the radial fiber (OSVZ progenitor) and the other that does not. The one that inherits
the radial fiber seems to repeat asymmetric cell division multiple times, while the
other differentiates into postmitotic neurons. The former cells (OSVZ progenitors)
express Hes1, and inhibition of Notch signaling by treatment with a γ-secretase
inhibitor induces OSVZ progenitors to differentiate into neurons or Tbr2+ basal
progenitors (Hansen et al. 2010), suggesting that Notch signaling is required for
maintenance of OSVZ progenitors (Fig. 1.6). Interestingly, these daughter cells
(OSVZ progenitor and neuron) maintain contact with each other for several hours,
and neurons express Notch ligands and activate Notch signaling in their sibling
OSVZ progenitors (Fig. 1.6) (Shitamukai et al. 2011). These observations suggest
that asymmetric cell division is required to activate Notch signaling in OSVZ pro-
genitors by their sibling neurons.
OSVZ progenitors seem to play a major role in the increase of the neuronal num-
ber in the cortex, and indeed it was shown that the developing human neocortex has
an expanded outer region in the SVZ, suggesting that OSVZ progenitors are respon-
sible of the expansion of the cortex. It is possible that the cells that migrate into the
SVZ may become OSVZ progenitors when Notch signaling is active, whereas they
may become basal progenitors when Notch signaling is inactive. It remains to be
determined how Notch signaling is regulated in the SVZ and whether Hes1 expression
oscillates in OSVZ progenitors, as observed in radial glial cells.
1.6 Sustained Hes1 Expression in Boundary Cells
The developing nervous system is partitioned into many compartments by boundaries

such as the isthmus and the zona limitans intrathalamica (Fig. 1.7). The nervous
system is also partitioned into the right and left halves by the roof plate and the floor
plate (Fig. 1.7). These boundaries function as the signaling centers by expressing
signaling molecules such as Fgf8, Shh, and Wnt and regulate specification of neural
progenitor cells and neurons in neighboring compartments (Kiecker and Lumsden
2005). Cells in these boundaries do not proliferate actively or usually do not give
rise to neurons. Thus, the proliferation and differentiation characteristics are different
between boundary cells and neural progenitor cells.
Fig. 1.7 Different expression dynamics of Hes1 in the developing nervous system. The develop-
ing nervous system is partitioned into many compartments by boundaries such as the isthmus and
the zona limitans intrathalamica (Zli). The nervous system is also partitioned into the right and left
halves by the roof plate and the floor plate. Cells in boundary regions are mostly dormant with
regard to proliferation and differentiation, in contrast to neural progenitor cells present in compart-
ments. Boundary cells express Hes1 in a sustained manner, while neural progenitor cells present in
compartments express Hes1 in an oscillatory manner
Cells in boundary regions express Hes1 in a sustained manner, which suppresses

proneural gene expression (Fig. 1.7) (Baek et al. 2006). It was found that the
retrovirus-mediated introduction of sustained Hes1 expression into neural progenitor
cells inhibits their proliferation and neuronal differentiation (Baek et al. 2006).
Sustained Hes1 expression downregulates not only Notch ligand and proneural
genes but also cell cycle regulators such as cyclin D1 and cyclin E2 (Shimojo et al.
2008). By contrast, when Hes genes are inactivated, boundaries are not properly
maintained, and cells in the boundary regions can express proneural genes and dif-
ferentiate into neurons (Hirata et al. 2001; Baek et al. 2006). These results suggest
that cells with sustained Hes1 expression are rather dormant with regard to prolif-
eration and differentiation and that oscillatory expression of Hes1 may be important
for proliferation and differentiation of neural progenitor cells. This feature is similar
to the one observed in fibroblasts, where sustained Hes1 overexpression leads to
reversible quiescence (Sang et al. 2008).
The mechanism by which oscillatory versus sustained Hes1 expression is regu-
lated remains to be determined. In fibroblasts, Jak-Stat signaling is involved in Hes1
oscillations. Jak2 activates Stat3 by phosphorylation, and phosphorylated Stat3
(pStat3) induces Socs3 expression, which in turn inhibits Jak2. Due to this negative
feedback, pStat3 and Socs3 levels oscillate in fibroblasts (Yoshiura et al. 2007).
Interestingly, blockade of this pathway with a Jak inhibitor inhibits Hes1 oscilla-
tions by stabilizing the Hes1 protein, and Hes1 expression becomes steady in fibro-
blasts (Yoshiura et al. 2007). Similarly, treatment with a Jak inhibitor inhibits Hes1
oscillations in neural progenitor cells, suggesting that Jak-Stat signaling is also
involved in the regulation of Hes1 oscillations in these cells (Shimojo et al. 2008).
It was shown that the Id-mediated regulation is involved in sustained expression
of Hes1. Id proteins, HLH factors without a basic region, form heterodimers with
Hes1 through their HLH domains and inhibit Hes1 from binding to the N box in the
Hes1 promoter (Bai et al. 2007), suggesting that Id factors prevent Hes1 from nega-
tive autoregulation. Thus, Id proteins could inhibit the oscillatory expression of
Hes1, although it remains to be determined whether Id factors lead to steady Hes1
expression in boundaries.
Another possible mechanism is microRNA-9 (miR-9), which interacts with the
3′-untranslated region (UTR) sequence of Hes1 mRNA. MiR-9 is important for the
short half-life of Hes1 mRNA and downregulation of Hes1 protein expression.
Interestingly, knockdown of miR-9 inhibits the oscillatory expression of Hes1
(Bonev et al. 2012; Tan et al. 2012b). Because it was previously shown that the
instability of gene products is essential for continuous oscillation of Hes7, another
member of the Hes family (Hirata et al. 2004), it is likely that miR-9-induced short
half-life of Hes1 mRNA may be required for Hes1 oscillation. Expression analyses
showed that miR-9 is highly expressed in the ventricular zone, where neural pro-
genitor cells reside, whereas it is absent in boundary regions (Tan et al. 2012b),
suggesting that the lack of miR-9 expression leads to sustained expression of Hes1
in boundaries.
1.7 Downstream Events of Hes1 and Neurog2 Oscillations
Some downstream genes such as Dll1 are expressed in an oscillatory manner via
periodic repression by Hes1 and periodic activation by Neurog2. Other downstream
genes could be gradually up- or downregulated over time in response to Hes1 and
Neurog2 oscillations, which could lead to changes in competency of neural progeni-
tor cells (Fig. 1.8). It was previously shown that sustained overexpression of Hes1
or Hes5 accelerates astrocyte formation (Ohtsuka et al. 2001), raising the possibility
that compared to Hes1 oscillation, sustained Hes1 expression accelerates the transi-
tion from neurogenesis to astrogenesis. Identification of downstream genes for Hes1
will be required to understand the mechanism of how such transition is controlled.
One candidate gene involved in the transition from neurogenesis to astrogenesis
is ESET/Setdb1/KMT1E, a histone H3 Lys-9 (H3K9) methyltransferase gene,
Fig. 1.8 Possible downstream events of Hes1 and Neurog2 oscillations. Some downstream genes
could be gradually up- or downregulated over time in response to Hes1 and Neurog2 oscillations,
which could lead to changes in competency of neural progenitor cells during development. ESET
expression in neural progenitor cells is gradually downregulated, and this gene expression could be
regulated by Hes1 and Neurog2 oscillations
because this gene has multiple Hes1-binding sites in the promoter, although it
remains to be determined whether Hes1 regulates ESET expression. ESET is highly
expressed by neural progenitor cells at early stages of development, but the expres-
sion is downregulated over time and becomes significantly low or almost absent at
later stages when the transition from neurogenesis to astrogenesis occurs (Tan et al.
2012a). Inactivation of ESET in the forebrain derepresses the expression of endog-
enous retrotransposons and their neighboring genes as well as non-neural gene
expression and leads to impairment of formation of early-born (deep layer) neurons
and enhancement of astrocyte formation. Formation of late-born (superficial layer)
neurons is also accelerated because of impairment of early neurogenesis, but
because astrocyte formation is also accelerated, the final number of late-born neu-
rons is mostly normal (Tan et al. 2012a). Conversely, overexpression of ESET
decreases the astrocyte differentiation. These results suggest that decreasing expres-
sion of ESET during development may be one of the internal clock mechanisms that
regulate the timing of cell fate switches of neural progenitor cells, from deep layer
neurogenesis to superficial layer neurogenesis and finally to astrogenesis. Further
analyses will be required to determine whether Hes1 oscillation is involved in gradual
downregulation of ESET.
1.8 Conclusions
Oscillatory versus sustained Hes1 expression leads to different outcomes in neural

progenitor cells. When its expression oscillates, neural progenitor cells proliferate
actively and differentiate into mature cells. By contrast, when its expression is sus-
tained, neural progenitor cells become dormant. Adult neural stem cells are known
to be mostly dormant, suggesting that Hes1 expression is non-oscillatory. If this is
the case, it would be interesting to induce Hes1 oscillation in these cells to see
whether adult neural stem cells are activated in proliferation. Similarly, oscillatory
versus sustained Neurog2 expression leads to different outcomes. When its expres-
sion is sustained, neural progenitor cells differentiate into neurons. By contrast,
when its expression oscillates, neural progenitor cells remain undifferentiated.
Thus, not just the expression but the dynamics of these genes are very important for
the outcomes. Oscillatory versus sustained Hes1 expression is regulated by Jak-Stat
signaling, Id, and miR-9, although the exact mechanism remains to be determined.
Oscillatory versus sustained Neurog2 expression is regulated by Hes1. However,
the dynamics of downstream genes for Hes1 and Neurog2 oscillations are mostly
unknown. The expression of some genes may be gradually up- or downregulated
over time in response to Hes1 and Neurog2 oscillations, which could be responsible
for changes in differentiation competency of neural progenitor cells. Further analysis
of the downstream events will be required to understand the complex regulatory
mechanism of neural development.
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Chapter 2
Proneural Proteins and the Development
of the Cerebral Cortex
Julian Heng and François Guillemot
Abstract Proneural transcription factors are key regulators of neurogenesis.

This chapter focuses on the proneural proteins Ascl1, Neurog1 and Neurog2 and
their multiple roles in development of the mammalian cerebral cortex. The first part
of the chapter considers the different aspects of telencephalic development that are
regulated by proneural proteins, including the neuronal versus glial fate decision, the
specification of glutamatergic and GABAergic neuronal phenotypes, and the radial
migration, dendritic morphogenesis and axonal projection patterning of cortical
neurons. The second part turns to the molecular mechanisms through which proneu-
ral proteins exert their activities and discusses the regulation of their expression and
activity, the identification of the many genes they regulate and finally the nature of
the transcription factors and cofactors that they interact with to regulate gene expres-
sion. Together, this chapter illustrates how studies focused on the functions and
modes of action of a small group of proteins have greatly improved our general
understanding of cortical development.
2.1 Introduction
Proneural proteins comprise a small group of transcription factors that have unique
and crucial functions in neurogenesis throughout the animal kingdom. They belong
to the vast class of basic-helix-loop-helix (bHLH) proteins, which are characterized
by a short stretch of basic amino acids conferring sequence-specific DNA-binding
J. Heng
Australian Regenerative Medicine Institute, Monash University, Wellington Road,
Clayton, VIC 3800, Australia
F. Guillemot (*)
Division of Molecular Neurobiology, MRC-National Institute for Medical Research,
The Ridgeway, Mill Hill, NW71AA London, UK
e-mail: [email protected]
R. Kageyama and T. Yamamori (eds.), Cortical Development: Neural Diversity 19

and Neocortical Organization, DOI 10.1007/978-4-431-54496-8_2, © Springer Japan 2013
20 J. Heng and F. Guillemot
activity and an adjacent helix-loop-helix region involved in dimerization with other

bHLH proteins (Massari and Murre 2000). Many bHLH transcription factors have
important functions in the generation and differentiation of tissues in both animal
and plant organisms.
There are two clearly distinct groups of bHLH proteins that are specifically
expressed within the developing nervous system, proneural factors and neuronal
differentiation factors, which differ in both expression patterns and loss-of-function
phenotypes. Proneural factors are expressed almost exclusively in progenitor cells
and they specify neuronal fates and initiate differentiation programmes. Neuronal
differentiation factors are expressed in postmitotic neurons and in some cases in
committed but still mitotic neuronal progenitors and are involved in the execution
of the differentiation programmes. It is worth noting that these two categories of
proteins cannot be distinguished by their gain-of-function phenotypes as both can
induce the formation of new neurons when ectopically expressed in competent cells
(e.g. Lee et al. 1995; Farah et al. 2000). In mammals, proneural bHLH factors
expressed in the telencephalon comprise just three proteins, the Achaete-Scute-like
factor Ascl1/Mash1 and the two Neurogenin factors Neurog1 and Neurog2. On the
other hand, the neuronal differentiation bHLH factors of the telencephalon com-
prise six factors, including four Neurod proteins, Neurod1, Neurod2, Neurod4 and
Neurod6, and two Nscl proteins, Nscl1 and Nscl2.
This chapter focuses on the role of the proneural proteins Ascl1, Neurog1 and
Neurog2 in the development of the mammalian cerebral cortex. Within the embryonic
telencephalon, Neurog1 and Neurog2 are specifically expressed in the dorsal division
that produces all cortical projection neurons, while Ascl1 is expressed mostly in the
ventral division, which produces cortical interneurons as well as all basal ganglia neu-
rons. We will also discuss a few studies performed in other regions of the nervous
system, which provide important information on proneural proteins, relevant to their
role in cortical development. Not included here is a discussion of the role of proneural
factors in direct reprogramming, such as the conversion of non-neural cells including
fibroblasts and hepatocytes into neurons by forced expression of Ascl1 (Vierbuchen
et al. 2010; Marro et al. 2011; Pang et al. 2011). These studies have obviously impor-
tant medical implications, e.g. by providing a source of human neurons for modelling
disease processes, but how relevant the reprogramming process is to the normal func-
tion of proneural proteins remains an open question.
In the first part of this chapter, we will discuss the main cellular functions that
have been ascribed to proneural proteins during telencephalic development, namely,
the regulation of the neuronal versus glial fate decision (Sect. 2.2.1), the specifica-
tion of glutamatergic and GABAergic neuronal phenotypes (Sects. 2.2.2 and 2.2.3)
and the regulation of the radial migration, dendritic morphology and axonal projec-
tion pattern of cortical projection neurons (Sects. 2.2.4 and 2.2.5). In the second
part, we will turn to the molecular mechanisms through which proneural proteins
exert their activities and account for their functional diversity, including the
mechanisms that regulate the expression and activity of proneural proteins spa-
tially and temporally (Sect. 2.3.1), the nature of the transcriptional targets of
proneural proteins (Sect. 2.3.2) and finally the nature of the transcription factors
2 Proneural Proteins and the Development of the Cerebral Cortex 21
and cofactors that proneural proteins interact with to regulate gene expression
(Sects. 2.3.3 and 2.3.4). We hope that this chapter will provide an accurate and
up-to-date overview of the central role that these fascinating molecules have in the
development of the cerebral cortex.
2.2 Cellular Functions of Proneural Genes in Telencephalic

Development
2.2.1 Proneural Genes and the Neuronal Versus Glial Fate

Decision
The main cell type expressing proneural proteins in the developing telencephalon is
radial glial stem cells. Radial glial cells divide asymmetrically and self-renew while
generating postmitotic neurons or mitotic neuronal precursors. They convert into
astroglial precursors at the end of the neurogenic period. Proneural proteins have
redundant roles in controlling the neuronal specification of radial glial progenitors
(Fig. 2.1). As a result, mice carrying mutations in a single proneural gene have rela-
tively mild phenotypes compared with mice with mutations in two proneural genes.
Embryos mutant for Ascl1 alone lack radial glial cells in a defined region of the
ventral telencephalon, the medial ganglionic eminence, and lack also neuronal pop-
ulations derived from the missing progenitors (Casarosa et al. 1999). Neurog2
single mutant embryos have lost many neurons in the subplate and layers 6 and 5 of
the cortical plate. These defects are exacerbated in Neurog1, Neurog2 double mutants,
while Neurog1 single mutant mice do not present overt defects (Fode et al. 2000; Nieto
et al. 2001). Embryos that are mutant for both Ascl1 and Neurod4 present a severe
reduction of neurogenesis as well as ectopic astrogliogenesis in the midbrain and hind-
brain, while single mutants present only subtle defects in these structures (Tomita et al.
2000). Similarly, loss of both Neurog2 and Ascl1 results in a profound deficit in neuro-
nal production coupled with premature initiation of astroglial generation in the embry-
onic cortex (Nieto et al. 2001). Importantly, analysis of clonal cultures of mutant
cortical progenitors demonstrated that either Neurog2 or Ascl1 is required in radial
glial cells of the dorsal telencephalon to maintain their neurogenic potential and
prevent activation of the gliogenic programme (Nieto et al. 2001).
Analysis of the molecular mechanisms underlying Neurog1 activity in cortical
progenitors demonstrated that this factor induces neurogenesis and inhibits glial
differentiation via two distinct mechanisms (Sun et al. 2001). While induction of
neurogenesis involves a classical mode of transcriptional regulation requiring DNA
binding of Neurog1, the suppression of glial differentiation did not require DNA
binding but the sequestration of a complex formed by the transcription factor Smad1
and the cofactor CREB-Binding Protein (CBP) to prevent association of this
complex with STAT transcription factors for activation of the promoters of the
astrocyte-specific genes S100β and GFAP (Sun et al. 2001). Therefore, the function
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For these two points cf. H. vii. 152.
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94 banaustic banausic 1
fn 5 at Lade at Ladé 1
140 Kaikos Kaïkos 1
219 H. viii. 82. H. vii. 82. 1
219 H. viii. 91. H. vii. 97. 2
fn 114 negociated negotiated 1
382 H. vii. 76. H. viii. 76. 1
408 PERSAIN COUNCIL PERSIAN COUNCIL 3
fn 199 H. ix. 26 H. ix. 31 2
fn 199 Chapter 25 Chapter 30 2
fn 232 infornation information 2
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Cortical Development Neural Diversity and Neocortical Organization 1st Edition Hiromi Shimojo Download PDF

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Cortical Development Neural

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Management for Sustainable and Inclusive Development in

Semi empirical Neural Network Modeling and Digital

Self organizing Neural Maps The Retinotectal Map and

Diversity Intelligence: Integrating Diversity

Enacting Values-Based Change: Organization Development

A System of Health Accounts 2011 Organization For

Evaluating organization development : how to ensure and

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1 Dynamic Notch Signaling in Neural Progenitor Cells ......................... 1

10 The Roles of RECK, a Membrane-Anchored Regulator

Index ................................................................................................................. 277

Hiromi Shimojo, Yuki Maeda, Toshiyuki Ohtsuka, and Ryoichiro Kageyama

Abstract Notch signaling plays an essential role in maintenance of neural

H. Shimojo • R. Kageyama (*)

R. Kageyama and T. Yamamori (eds.), Cortical Development: Neural Diversity 1

Keywords Basal progenitor • Neuroepithelial cell • Oscillatory expression • OSVZ

1.2 The Core Pathway of Notch Signaling

Notch signaling plays an important role in cell proliferation and differentiation by

1.3 Oscillatory Expression of Notch Signaling Genes

expression of Dll1, which upregulates Hes1 expression in neighboring cells,

1.4 The Mechanism of Oscillatory Expression:

1.5 Basal Progenitors and Outer Subventricular Zone

1.6 Sustained Hes1 Expression in Boundary Cells

The developing nervous system is partitioned into many compartments by boundaries

Cells in boundary regions express Hes1 in a sustained manner, which suppresses

1.7 Downstream Events of Hes1 and Neurog2 Oscillations

Oscillatory versus sustained Hes1 expression leads to different outcomes in neural

Akazawa C, Sasai Y, Nakanishi S, Kageyama R (1992) Molecular characterization of a rat negative

Hirata H, Yoshiura S, Ohtsuka T, Bessho Y, Harada T, Yoshikawa K, Kageyama R (2002)

Niwa Y, Shimojo H, Isomura A, González A, Miyachi H, Kageyama R (2011) Different types of

Julian Heng and François Guillemot

Abstract Proneural transcription factors are key regulators of neurogenesis.

R. Kageyama and T. Yamamori (eds.), Cortical Development: Neural Diversity 19

activity and an adjacent helix-loop-helix region involved in dimerization with other

2.2 Cellular Functions of Proneural Genes in Telencephalic

2.2.1 Proneural Genes and the Neuronal Versus Glial Fate

The following corrections have been applied to the text:

Updated editions will replace the previous one—the old editions

Creating the works from print editions not protected by U.S.

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