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First published online 28 February 2007
doi: 10.1242/dev.000786
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Primer |
Institute for Virus Research, Kyoto University and Japan Science and Technology Agency, CREST, Kyoto 606-8507, Japan.
* Author for correspondence (e-mail: rkageyam{at}virus.kyoto-u.ac.jp)
SUMMARY
Embryogenesis involves orchestrated processes of cell proliferation and differentiation. The mammalian Hes basic helix-loop-helix repressor genes play central roles in these processes by maintaining progenitor cells in an undifferentiated state and by regulating binary cell fate decisions. Hes genes also display an oscillatory expression pattern and control the timing of biological events, such as somite segmentation. Many aspects of Hes expression are regulated by Notch signaling, which mediates cell-cell communication. This primer describes these pleiotropic roles of Hes genes in some developmental processes and aims to clarify the basic mechanism of how gene networks operate in vertebrate embryogenesis.
Introduction
Embryogenesis depends on the timely proliferation of progenitor cells and their subsequent differentiation into multiple cell types. Regulation of the timing of cell differentiation and cell fate choice are key issues for making organs of the right size, shape and cell composition. In many organs, cell proliferation and differentiation are antagonistically regulated by multiple basic helix-loop-helix (bHLH) activator and repressor genes. In particular, the Hes bHLH repressor genes play an essential role in the development of many organs by maintaining progenitor cells and by regulating binary cell fate decisions. For example, in the developing nervous system of mouse embryos, progenitor cells proliferate and sequentially give rise to different types of cells by changing their differentiation competency. Without Hes genes such as Hes1, however, progenitor cells prematurely differentiate into certain types of neurons only, and are depleted before they have proliferated sufficiently and generated all neuronal and glial cell types. This results in small and deformed brain structures. Hes genes also function as biological clocks, measuring time in developmental events, such as somite segmentation. In these processes, Hes genes function as effectors of Notch signaling, which coordinates cellular events via cell-cell interactions.
In this primer, we describe the key features of Hes factors and detail their roles in some representative processes of embryogenesis: namely, in the development of the nervous and digestive systems, two well-characterized processes, where Hes1 (and Hes3 and Hes5 in the nervous system) regulates cell proliferation and differentiation, and in the process of somite segmentation, where Hes7 functions as a biological clock. We will mainly focus on the roles of the mouse Hes genes, but also compare them with the zebrafish Hes genes (called the her family of genes) (Table 1).
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Hes genes are mammalian homologs of the Drosophila genes hairy and Enhancer of split [E(spl)]. There are seven members in the Hes family (Hes1-7), although Hes4 is absent in the mouse genome (Table 1). Hes genes encode nuclear proteins that repress transcription both actively and passively. In this section, we describe the structural and transcriptional features of Hes factors.
Conserved functional domains of Hes factors
Three conserved domains confer transcriptional functions on all Hes
factors: the bHLH, Orange and WRPW domains
(Fig. 1A). The bHLH domain
consists of two regions: the basic region for DNA binding and the
helix-loop-helix region for dimerization. Unlike most other bHLH factors, Hes
factors have a proline residue in the middle of the basic region. This proline
is proposed to confer to Hes factors unique DNA-binding activity. Most bHLH
factors bind to a consensus sequence called the E box (CANNTG) that is present
in the promoter region of their target genes. This sequence is further
classified into two groups: class A and class B. However, Hes factors bind
with highest affinity to different target sequences than the other bHLH
factors. These sequences are called the class C site CACG(C/A)G or the N box
CACNAG (Akazawa et al., 1992
;
Sasai et al., 1992;
Ohsako et al., 1994). The
Orange domain has two amphipathic helices and regulates the selection of bHLH
heterodimer partners (Dawson et al.,
1995; Taelman et al.,
2004). The C-terminal WRPW domain, which consists of the
tetrapeptide Trp-Arg-Pro-Trp, represses transcription. This sequence also acts
as a polyubiquitylation signal (Kang et
al., 2005): Hes factors are polyubiquitylated and degraded by the
proteasome, and thus they have very short half-lives (
20 minutes)
(Hirata et al., 2002). These
domains endow Hes factors with unique features as repressors and
oscillators.
Hes factors as repressors
Hes factors repress transcription by at least two different mechanisms:
active and passive repression (Fig.
1B,C) (Sasai et al.,
1992). Active repression depends on the WRPW domain, which
interacts with the co-repressors encoded by the Transducin-like E(spl) (TLE)
genes/Groucho-related gene (Grg), homologs of Drosophila
groucho (Paroush et al.,
1994; Fisher et al.,
1996; Grbavec and Stifani,
1996). It is known that chromatin is activated by histone
acetyltransferase and inactivated by histone deacetylase, and it has been
shown that Drosophila Groucho inhibits transcription by recruiting
histone deacetylase. Thus, it is likely that the Hes-Groucho-homolog complex
represses transcription by inactivating chromatin (active repression,
Fig. 1B). Hes factors not only
form homodimers, but they also form heterodimers with other bHLH repressors,
such as Hey1 (Hes-related with YRPW motif1) and Hey2. Heterodimers of Hes1 and
Hey1 or Hey2 bind to the class C site at their targets with a higher affinity
and repress transcription more efficiently than homodimers do
(Fig. 1B)
(Iso et al., 2001). Hes
factors also form heterodimers with bHLH activators that bind to the E box.
However, these heterodimers cannot bind to DNA
(Fig. 1C). Thus, Hes factors
display a dominant-negative effect on E box-binding bHLH activators (passive
repression).
Direct targets for Hes1 include the bHLH activators Mash1 (also known as
Ascl1 - Mouse Genome Informatics) and E47 (also known as Tcfe2a - Mouse Genome
Informatics), which are the mammalian homologs of the proteins encoded by the
Drosophila proneural genes achaete-scute complex (also known
as Cyp4g1 - FlyBase) and daughterless, respectively. Mash1
can form a heterodimer with E47 and activate neuronal-specific gene expression
by binding to the E box (Fig.
1D) (Johnson et al.,
1992), whereas Hes1 inhibits Mash1 and E47 activities by forming
non-DNA-binding heterodimers with them (passive repression,
Fig. 1C). Furthermore, Hes1
represses Mash1 expression by directly binding to the class C site in
the Mash1 promoter (active repression;
Fig. 1B)
(Chen et al., 1997).
Similarly, in the developing pancreas, Hes1 actively and passively inhibits
other bHLH activators, such as pancreas specific transcription factor
1a (Ptf1a) and neurogenin 3 (Ngn3, also known
as Neurog3), which specify exocrine and endocrine cell fates,
respectively (Lee et al.,
2001; Fukuda et al.,
2006), as discussed in more detail below.
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|
Hes genes regulate the maintenance of stem cells and progenitors and the normal timing of cell differentiation by antagonizing the effects of bHLH activators. Here, we describe roles for Hes genes in the nervous and digestive systems.
Hes genes regulate the maintenance of stem cells in neural development
During neural development, neuroepithelial cells form the neural plate and
proliferate by symmetric cell division
(Fig. 2A)
(Fishell and Kriegstein, 2003;
Götz and Huttner, 2005).
As development proceeds, neuroepithelial cells become radial glial cells,
which have a cell body in the ventricular zone and a radial fiber reaching the
pial surface (Fig. 2A). Both
neuroepithelial and radial glial cells are considered to be embryonic neural
stem cells. Radial glial cells undergo asymmetric cell divisions, giving rise
to a further radial glial cell and a neuron or neuronal precursor
(Fishell and Kriegstein, 2003;
Götz and Huttner, 2005).
Radial glial cells can change their competency and can generate distinct types
of neurons over time. In the mouse cortex, different neurons migrate along
radial fibers to settle in different layers: early-born neurons in deeper
layers and later-born neurons in more-superficial layers. After the production
of neurons, radial glial cells can differentiate into oligodendrocytes and
finally into astrocytes (Fig.
2A) (Fujita,
2003). Hes1 and Hes3 are widely expressed by
neuroepithelial cells, whereas Hes1 and Hes5 are mainly
expressed by radial glial cells (Fig.
2A), although there is some redundancy between the Hes genes
(Hatakeyama et al., 2004).
Misexpression of Hes1 or Hes5 in the developing mouse
brain at embryonic day (E) 13.5 inhibits neuronal differentiation and
maintains a radial glial cell identity
(Fig. 2B)
(Ohtsuka et al., 2001). In the
absence of Hes1 and Hes5, radial glial cells are not
maintained and prematurely differentiate into neurons. Despite the correct
formation of neuroepithelial cells in Hes1; Hes3; Hes5
triple-knockout mice, these cells prematurely differentiate into early-born
types of neurons and become depleted without giving rise to the later-born
cell types (Hatakeyama et al.,
2004). Thus, Hes genes maintain neural stem cells until later
stages of mouse development, ensuring that sufficient numbers of cells with a
full cell-type diversity are generated. In these Hes-mutant mice, proneural
bHLH genes, such as Mash1 and Ngn2 (also known as
Neurog2), are highly upregulated, which accounts for the premature
neurogenesis (Hatakeyama et al.,
2004). The intracellular domain of Notch (NICD), which is
constitutively active, also promotes the maintenance of radial glial cells by
inhibiting neurogenesis (Gaiano et al.,
2000). However, in the absence of Hes1 and Hes5,
the NICD cannot inhibit neurogenesis, indicating that Hes1 and
Hes5 are essential effectors of Notch signaling in the nervous system
(Box 1 and Table 1)
(Ohtsuka et al., 1999).
Strikingly, in Hes1; Hes5 double-knockout mice, the optic
vesicles, which are normally formed on the right and left sides of the
diencephalon, are absent (Hatakeyama et
al., 2004). In the presumptive eye regions, non-retinal neurons
prematurely differentiate as early as E9.5, although no neurogenesis normally
occurs in the wild-type optic vesicles at this stage
(Hatakeyama et al., 2004).
Thus, retinal stem cells/progenitors are neither maintained nor properly
specified in the absence of Hes1 and Hes5.
The other Hes genes (Hes2 and Hes6) are also expressed in
the developing nervous system, but the expression and function of
Hes6 is unique among the Hes genes. Unlike Hes1, Hes3 and
Hes5, Hes6 is expressed by differentiating neurons. Furthermore, Hes6
inhibits Hes1 by forming a non-functional heterodimer, which supports Mash1
activity, and thereby promotes neuronal differentiation
(Fig. 2A and
Table 1)
(Bae et al., 2000).
Hes genes regulate boundary formation
The developing nervous system is partitioned into many compartments by
boundaries, such as the zona limitans intrathalamica (Zli) and the isthmus
(Fig. 3A). The Zli is the
boundary between the thalamus and the prethalamus, whereas the isthmus is the
boundary between the midbrain and the hindbrain. Boundaries are formed by
specialized neuroepithelial or radial glial cells, which have unique features,
including slow proliferation, delayed or no neurogenesis and organizer
activities that regulate specificity of neighboring compartments. For example,
the Zli and the isthmus function as organizing centers by secreting sonic
hedgehog and Fgf8, respectively, and by regulating the regional specification
of neighboring compartments (Kiecker and
Lumsden, 2005) (Fig.
3A). Cells migrate within each compartment but do not usually
cross boundaries; thus, each compartment forms a unit that consists of a
distinct set of cell types (Kiecker and
Lumsden, 2005). Although Hes1 is expressed in both
compartments and boundaries, the mode of expression is different in the two
structures (Baek et al., 2006).
In compartments, Hes1 levels are variable: high levels occur in some cells,
whereas, in others, levels are lower (Fig.
3Ba) (Baek et al.,
2006). Hes1 levels could be oscillating in these cells (see
below). By contrast, Hes1 is persistently expressed at high levels by many
boundary cells (Fig. 3Bb)
(Baek et al., 2006). There is
an inverse correlation between Hes1 and Mash1 levels: cells that express high
levels of Hes1 express low levels of Mash1 and vice versa
(Fig. 3B). Within boundaries,
persistent and high levels of Hes1 expression constitutively repress
the expression of proneural genes, such as Mash1, thereby inhibiting
neurogenesis (Fig. 3Bb)
(Baek et al., 2006). In the
absence of Hes genes, proneural genes are ectopically expressed in boundaries,
leading to ectopic neurogenesis and the loss of organizer activity
(Hirata et al., 2001;
Baek et al., 2006). In
zebrafish, her3 and her5 have similar activities, inhibiting
neurogenesis and contributing to the formation of the midbrain-hindbrain
boundary (Table 1). It has been
reported that the expression of her3 and her5 does not
depend on Notch signaling (Table
1), suggesting that Hes expression in boundaries of the mouse
nervous system could also be independent of this pathway.
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| Box 1. Notch signaling
Notch family members are type I transmembrane receptors for the DSL (Delta,
Serrate, Lag-2) family of type I transmembrane ligands
(Artavanis-Tsakonas et al.,
1999
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It has been shown that Hes1 regulates cell cycle progression. During the G1
phase, cyclin-dependent kinase (CDK) promotes cell cycle progression by
forming complexes with cyclins, whereas the CDK inhibitors p21 and p27
antagonize this process. Low levels of Hes1 promote cell proliferation by
downregulating p21 and p27 (Murata et al.,
2005). However, persistent and high levels of Hes1
expression have been shown to inhibit the cell cycle, probably because Hes1
also represses the expression of some cell cycle regulators such as E2F-1,
which promotes the G1-S phase transition
(Castella et al., 2000;
Ström et al., 2000;
Hartman et al., 2004;
Baek et al., 2006). Thus,
within boundaries, persistent and high levels of Hes1 expression may
contribute to slowing cell proliferation as well as to the inhibition of
differentiation, raising the possibility that persistent versus variable
Hes1 expression differentially regulates boundary versus compartment
characteristics (Fig.
3B).
Hes1 regulates the maintenance of stem cells and progenitors in digestive organs
The dorsal and ventral pancreatic buds, which fuse to form the pancreas,
grow from the endodermal epithelium of the foregut
(Murtaugh, 2007). The
pancreatic epithelium gives rise to both exocrine and endocrine cells:
exocrine progenitors become acinar cells, which secrete digestive enzymes,
whereas endocrine cells emigrate from the epithelium to form islets
(Fig. 4A). The liver and
biliary systems also originate from the endodermal epithelium of the foregut.
Thus, the gut, pancreas, liver and biliary systems share the same origin.
In the developing pancreas, the bHLH gene Ptf1a promotes exocrine
cell differentiation, whereas the bHLH gene Ngn3 promotes the
differentiation of all four endocrine cell types [
(glucagon-producing), ß (insulin-producing), 
(somatostatin-producing) and PP (pancreatic polypeptide-producing) cells]
(Fig. 4A)
(Krapp et al., 1998;
Gradwohl et al., 2000;
Kawaguchi et al., 2002).
Inactivation of Hes1 in mice leads to the upregulation of
Ngn3, an acceleration of post-mitotic endocrine cell differentiation
and severe pancreatic hypoplasia (Jensen
et al., 2000). Similar defects are observed following inactivation
of the Notch ligand delta-like 1 (Dll1) or the Notch effector Recombination
signal sequence-binding protein (RBP-J) (Box 1), or by the overexpression of
Ngn3 (Apelqvist et al.,
1999), suggesting that the Dll1-Notch-RBP-J-Hes1 pathway inhibits
premature endocrine differentiation. Hes1 also represses Ptf1a
expression by directly binding to the promoter of this gene. Similarly, NICD
inhibits acinar cell differentiation by antagonizing Ptf1a function
(Hald et al., 2003;
Murtaugh et al., 2003;
Esni et al., 2004;
Fujikura et al., 2006). Thus,
Notch-Hes1 signaling promotes the maintenance of pancreatic stem
cells/progenitors by antagonizing Ptf1a and Ngn3
(Fig. 4A). Interestingly, in
Hes1-null mice, Ptf1a and Ngn3 are ectopically
expressed in the common bile duct, stomach and duodenum, leading to the
formation of an ectopic pancreas (Sumazaki
et al., 2004; Fukuda et al.,
2006).
|
). The
bHLH activator gene Math1, a mammalian homolog of the
Drosophila proneural gene atonal, promotes the development
of goblet, enteroendocrine and Paneth cells, whereas the activation of
Notch-Hes1 signaling represses Math1, and thereby inhibits the
generation of Math1-dependent cells
(Jensen et al., 2000;
Yang et al., 2001;
Suzuki et al., 2005;
van Es et al., 2005;
Fre et al., 2005;
Stanger et al., 2005). The
inactivation of Notch signaling in the adult intestine causes the loss of
Hes1 expression and the concomitant upregulation of Math1,
leading to the differentiation of virtually all crypt cells into postmitotic
goblet cells (van Es et al.,
2005). Thus, the Notch-Hes1 pathway regulates the maintenance of
stem cells/progenitors by repressing Math1.
Loss of the tumor suppressor gene adenomatosis polyposis coli
(Apc) is associated with the development of intestinal adenomas
(Kinzler et al., 1991).
Interestingly, these adenoma cells express Hes1 at high levels,
suggesting that the Notch-Hes1 pathway contributes to this transformation of
progenitor cells to adenomas. Strikingly, the treatment of mice with a
-secretase inhibitor, which inhibits Notch signaling by preventing the
release of the NICD, leads to the upregulation of Math1 and the
subsequent transformation of adenomas into collections of goblet cells
(van Es et al., 2005). Thus,
the Notch-Hes1 pathway also plays an important role in intestinal adenoma
development, and -secretase inhibitors may be useful for treating these
tumors (van Es et al.,
2005).
Hes genes regulate binary cell fate decisions
In addition to maintaining stem cells, Hes genes regulate binary cell fate
decisions. For example, they regulate the determination of an astrocyte versus
a neuronal fate, thereby generating cell type diversity
(Kageyama et al., 2005).
Hes1 and Hes5 regulate astrocyte versus neuron fate specification
During late development, Hes genes promote astrocyte formation in the
developing nervous system. It has been shown that proneural bHLH activators
such as neurogenin 1 (Ngn1, also known as Neurog1 - Mouse Genome Informatics)
have dual activities: they not only activate neuronal-specific gene
expression, but they also inhibit astrocyte-specific gene expression by
sequestering coactivators of these genes, such as p300
(Sun et al., 2001).
Furthermore, mice lacking proneural genes display a blockade of neurogenesis
and show accelerated formation of astrocytes at E15.5
(Tomita et al., 2000;
Nieto et al., 2001). Thus, one
of the mechanisms of Hes-induced astrocyte versus neuron fate specification is
through the inhibition of proneural bHLH activators. Hes1 can also induce
astrocyte development through another pathway. Lif (leukemia inhibitory
factor) and Bmp2 (bone morphogenetic protein 2) synergistically induce
astrocyte formation (Nakashima et al.,
1999; Kamakura et al.,
2004). Lif signaling activates the Janus kinase Jak2, which then
activates the downstream transcription factor Stat3 by phosphorylation. It has
been shown that Hes1 promotes Jak2-mediated phosphorylation of Stat3 by
forming a complex with Jak2 and Stat3. This then induces the differentiation
of astrocytes (Kamakura et al.,
2004). It remains to be determined, however, why Hes genes cannot
induce astrocyte formation at early stages of development. One possibility is
that the epigenetic status of astrocyte-specific genes is different between
the early and late neural stem cells; in early stem cells, transcription from
astrocyte-specific promoters is repressed by hypermethylation, whereas these
promoters are hypomethylated in later stem cells
(Takizawa et al., 2001). Thus,
the intrinsic properties of neural stem cells change over time, correlating
with their differential response to Hes genes.
|
; Suzuki et al.,
2005; van Es et al.,
2005). Similarly, in zebrafish, goblet and enteroendocrine cells
are formed at the expense of enterocytes by the inactivation of Notch
signaling (Crosnier et al.,
2005). Thus, it is likely that Notch-Hes1 signaling promotes the
enterocyte versus non-enterocyte specification, although the downregulation of
Notch signaling is required for the maturation of enterocytes.
Liver progenitors give rise to two types of cells: hepatocytes and biliary
epithelial cells. In the absence of Hes1, hepatocytes form normally,
whereas intrahepatic bile ducts are completely absent
(Kodama et al., 2004). This
phenotype is similar to that of Alagille syndrome, which is associated with
mutations in the human Notch ligand jagged 1
(Oda et al., 1997;
Li et al., 1997). Thus, it is
likely that the specification of a biliary fate versus a hepatocytic one is
brought about by Jagged-mediated Hes activity.
Hes genes are molecular oscillators
In mouse embryos, a bilateral pair of somites is formed every 2 hours,
indicating that an innate timing mechanism regulates this process
(Dubrulle and Pourquié,
2004). It has been shown that the expression of Hes1 and
Hes7 oscillates with a periodicity of 2 hours, and may function as a
biological clock; Hes1 seems to regulate the timing of biological
events in many cell types, such as fibroblasts, whereas Hes7
functions as the segmentation clock.
Hes1 is a cellular oscillator
Expression of Hes1 can be induced following serum stimulation or
Notch activation in many cell types, such as fibroblasts, myoblasts and
neuroblasts; however, strikingly, the induced expression is oscillatory
(Hirata et al., 2002). Hes1
oscillation is cell-autonomous and depends on negative autoregulation
(Fig. 5A). After induction,
Hes1 protein represses the expression of its own gene by directly binding to
its promoter. This repression is short-lived due to the short half-life of the
mRNA and protein. In this way, Hes1 autonomously initiates oscillatory
expression with a periodicity of approximately 2 hours, suggesting that Hes1
acts as a biological clock (Fig.
5A). This oscillation is transient and dampened after three to six
cycles (6-12 hours). However, this observation is not due to dampened
oscillation within individual cells, in which Hes1 expression is
still cyclical even after nearly 2 days, as revealed by real-time imaging
analysis (Masamizu et al.,
2006). Rather, the dampening arises because the oscillation period
varies from cycle to cycle within a cell, and, therefore, oscillations among
cells easily fall out of synchrony. This loss of synchrony explains why, after
several cycles, the oscillatory expression of Hes1 is not detected by
northern or western blot analysis. Similarly, even in stationary cultured
cells where Hes1 levels seem to be constant by northern and western blot
analyses, Hes1 expression is found to be dynamically changing at the
single-cell level (Masamizu et al.,
2006). Thus, at any given time, Hes1 expression levels
are variable within and between cells, which may enable a cell to mediate a
different response to the same stimulus. Hes1 oscillation may regulate the
timing of cellular events, such as the cell cycle, but its precise roles are
unknown.
|
). This event is repeated every 2 hours in mouse embryos. It
has been suggested that this periodic event is controlled by a biological
clock, called the segmentation clock. It was first reported that the
expression of chairy1, a chick homolog of mouse Hes1, is
periodically propagated in a wave-like fashion initiating at the posterior end
and moving towards the anterior region of the PSM (propagation is classified
into three phases; Fig. 5Bb)
(Palmeirim et al., 1997). Each
wave leads to the generation of a pair of somites. In the mouse PSM, Hes1,
Hes5 and Hes7 are expressed in a similar fashion to each other
(Fig. 5B), but Hes7 is
the most important for somite segmentation. This wave-like expression of
Hes7 is elicited by its oscillatory expression in each PSM cell
(Fig. 5Bc). In the absence of
Hes7, somites fuse, which results in fused vertebrae and ribs
(Bessho et al., 2001).
Interestingly, a lack of oscillation due to persistent Hes7
expression also leads to somite fusion
(Hirata et al., 2004). Thus,
oscillatory expression is very important for periodic somite segmentation. In
zebrafish, her1 and her7 have oscillatory expressions and
regulate somite segmentation (Table
1).
Hes7 oscillation, like that of Hes1, is regulated by negative feedback
(Fig. 5A)
(Bessho et al., 2003). One of
its downstream target genes is the glycosyltransferase lunatic fringe
(Lfng), which regulates Notch activity by glycosylation
(Moloney et al., 2000;
Brückner et al., 2000).
Hes7 protein represses transcription from the Lfng promoter as well
as from its own, and thus Lfng expression oscillates in phase with
Hes7 expression (Bessho et al.,
2003). In the absence of Hes7, Lfng is constitutively
expressed in the PSM (Bessho et al.,
2001). Lfng oscillation is also crucial for segmentation,
as both the loss of and persistent expression of Lfng has been shown
to lead to severe somite fusion (Evrard et
al., 1998; Zhang and Gridley,
1998; Serth et al.,
2003). Lfng periodically inhibits Notch signaling and thereby
generates oscillations in Notch activity
(Dale et al., 2003;
Morimoto et al., 2005;
Huppert et al., 2005), which
may in turn influence Hes7 oscillation. It is thought that the combined
effects of these coupled negative-feedback loops on Hes7 and
Lfng expression are important for sustained and synchronized
oscillations and for the correct timing of the biological clock.
Conclusion
It has been shown that Hes genes not only promote the maintenance of stem
cells/progenitors, but they also regulate the binary cell fate decisions in
many organs, only some of which are described here. Hes genes also regulate
the timing of several developmental events, such as somite segmentation.
Although Hes1 expression oscillates in many cell types, the
significance of this oscillation in non-PSM cells remains to be determined. In
mouse neural stem cells, Hes1 expression is variable, suggesting that
it oscillates in these cells. Real-time visualization of Hes1
expression supports this suggestion (R.K. and T.O., unpublished data).
However, the significance of Hes1 oscillations to stem cell proliferation and
differentiation is unclear. Although Hes1 is required for the
maintenance of stem cells, persistent and high levels of Hes1
expression inhibit both cell proliferation and differentiation
(Baek et al., 2006). Thus,
oscillatory expression may be important for stem cell maintenance.
Furthermore, recent studies have revealed that, other than the circadian clock
genes, Hes genes are not the only oscillators
(Nelson et al., 2004;
Lahav et al., 2004). This
raises the possibility that more genes may be identified that display
oscillatory expression, and that these oscillations could be a required
general feature of many cellular events. Our understanding of how gene
networks operate in cell proliferation and differentiation during development
is continually improving. It is now apparent that Hes genes play an
indispensable role in different developmental contexts, as well as in the
crucial maintenance of the biological clock.
ACKNOWLEDGMENTS
We thank Clare Garvey, Jane Alfred and two anonymous reviewers for their critical reading of the manuscript. This work was supported by the Grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
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