Howard Hughes Medical Institute, 545 Life Sciences Addition, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720-3200, USA e-mail: lai{at}fruitfly.org
SUMMARY
Notch is a transmembrane receptor that mediates local cell-cell communication and coordinates a signaling cascade present in all animal species studied to date. Notch signaling is used widely to determine cell fates and to regulate pattern formation; its dysfunction results in a tremendous variety of developmental defects and adult pathologies. This primer describes the mechanism of Notch signal transduction and how it is used to control the formation of biological patterns.
Introduction
The ability to form biological patterns is key to the orderly and
reproducible development of all multicellular life. Pattern formation is made
possible by molecular mechanisms of cell-cell signaling, which permit cells to
influence each other's fate and behavior. One of the most important mechanisms
of cell signaling is mediated by Notch, a transmembrane receptor that
coordinates a signaling system known as the Notch pathway. Notch was
identified genetically almost 100 years ago by a mutant fly with `notches' in
its wings (Morgan, 1917),
which indicated its requirement in wing outgrowth. Notch has since been found
to be crucial for patterning in a great number of other developmental settings
throughout the animal kingdom, from worms to humans.
This primer describes the key molecular features of Notch signaling and some representative biological processes that it controls by first introducing the core players and mechanism of Notch signal transduction; Notch is an unusual protein in that it functions both at the cell surface to receive extracellular signals and in the nucleus to regulate gene expression. In addition, some of the many biological settings where Notch signaling regulates cell fates and pattern formation are discussed, together with molecular strategies that influence Notch signaling in specific developmental locations. Finally, how the knowledge of Notch function and biology from model organism studies has lent insight into human diseases caused by aberrant Notch signaling is also considered.
Notch signaling: key players and mechanism
Core components of Notch signaling
Key components of Notch signaling were originally recognized genetically
through mutant animals whose phenotypes resembled those of Notch
mutants. In flies, Notch was the founding member of a collection of
`neurogenic' mutants (see Box 1), so named because they produce a remarkable
excess of neurons at the expense of epidermis
(Poulson, 1945;
Lehmann et al., 1983
).
Nematodes have two homologs of Notch (LIN-12 and GLP-1), which were identified
by mutations that affect cell lineages and germ-line proliferation. The
lin-12/glp-1 double mutant displays an aggregate phenotype
that constitutes the full loss of Notch activity in the worm; this phenotype
is characteristic of a small class of `LIN and GLP' or `LAG' mutants in worms
(Lambie and Kimble, 1991
).
These mutants laid the foundation for genetic, molecular and biochemical
studies that established the core Notch signaling apparatus. At its heart lies
a Delta-type ligand, a Notch-type receptor and a transcription factor of the
CBF1/Su(H)/LAG1 (CSL) family (Fig.
1). All metazoan organisms studied to date contain one or more
orthologs of each of these proteins, and these are summarized in
Table 1. Delta- and
Notch-related proteins are all single-pass transmembrane proteins that contain
extracellular arrays of epidermal growth factor (EGF) repeats; specific EGF
repeats mediate direct contact between ligand and receptor
(Rebay et al., 1991). CSL
proteins are sequence-specific DNA-binding proteins
(Henkel et al., 1994
) that
function downstream of Notch. Because almost all locations of Notch signaling
involve this ligand-receptor-transcription factor trio, they are generally
considered as the `core' components of Notch signaling.
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|
Box 1. Neurogenic genes The field of Notch signaling originated with the study of `neurogenic' fly embryos, which exhibit excessive neuronal differentiation. The term `neurogenic' has persisted over the decades: partly out of deference to history; and partly out of the efficacy of the neurogenic phenotype in continuing to identify new genes that are functionally connected to Notch signaling, even to this day. However, the term `neurogenic' has also been the source of some continuing confusion, as it might reasonably be assumed to refer to a gene that promotes neurogenesis and/or functions exclusively during neurogenesis. Therefore, it is important to understand that: (1) `neurogenic' describes a loss-of-function condition (thus, `neurogenic' genes actually serve to repress neurogenesis); and (2) `neurogenic' genes do not function exclusively during neurogenesis (rather, they usually operate throughout development).
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Two homes for the receptor Notch
Some signaling cascades are truly cascades, and involve a complicated
sequence of proteins that pass a message from the outside of the cell into the
nucleus. At the opposite end of the spectrum lies Notch signaling, which
operates by a remarkably direct mechanism. The route towards understanding how
Notch works, however, has not been so direct.
For many different types of signal-activated cell-surface receptors,
removal of the extracellular domain creates a mutant receptor that is
permanently in the active mode. This is the case for Notch: an artificial,
truncated Notch protein consisting of only its intracellular domain
(Notchintra) has strong constitutive activity in flies and worms
(Lieber et al., 1993;
Struhl et al., 1993
).
Interestingly, these engineered Notchintra proteins localized to
the nuclei of transgenic animals, which indicated that the transmembrane
receptor Notch might have a nuclear function. Consistent with this model, a
direct protein-protein interaction has been observed between
Notchintra and the CSL transcription factor
(Fortini and Artavanis-Tsakonas,
1994
). However, a competing model based upon tissue culture data
proposed that the purpose of Notch-CSL binding was to hold CSL in the
cytoplasm until receptor activation, at which point CSL would be released and
travel to the nucleus (Fortini and
Artavanis-Tsakonas, 1994
).
Both models were challenged by the locations of the natural proteins in
tissues engaged in Notch signaling: endogenous nuclear Notch is essentially
never seen, while CSL appears constitutively nuclear. Eventually, the evidence
came together to support strongly the Notch nuclear translocation model. The
key findings were: (1) that Notch is proteolyzed in response to its
interaction with ligand, which releases a soluble intracellular fragment (a
natural Notchintra molecule; see Box 2)
(Kopan et al., 1996;
Schroeter et al., 1998
;
Struhl and Adachi, 1998
); (2)
that Notchintra is a transcriptional co-activator
(Jarriault et al., 1995
;
Hsieh et al., 1996
); and (3)
that exceedingly small, histochemically invisible, amounts of
Notchintra suffice to activate target genes
(Schroeter et al., 1998
;
Struhl and Adachi, 1998
). The
current `canonical' view of Notch signaling is that ligand-induced activation
of Notch triggers the cleavage and liberation of a small amount of
Notchintra, which then translocates to the nucleus and serves as a
CSL transcriptional co-activator (Fig.
1, but see Box 3 for some examples of `non-canonical' Notch
signaling).
Notchintra flips a CSL transcriptional switch
If CSL proteins reside in the nucleus, do they do anything when Notch is at
the cell surface? CSL function was initially perplexing; vertebrate CSL
proteins were first characterized as transcriptional repressors
(Dou et al., 1994), but
genetic tests in flies showed that CSL activated target genes during Notch
signaling (Bailey and Posakony,
1995
; Lecourtois and
Schweisguth, 1995
). How can the same protein be both a repressor
and an activator?
Insight into this puzzle came from a virus. The EBNA2 protein from
Epstein-Barr Virus (EBV) is a transcriptional co-activator that binds to and
hijacks CSL in infected B cells. Interestingly, EBNA2 converts CSL from a
default repressor into an activator of transcription
(Hsieh and Hayward, 1995;
Waltzer et al., 1995
).
Notchintra was later found to use the same strategy
(Jarriault et al., 1995
;
Hsieh et al., 1996
). The basis
of this switch involves distinct CSL co-repressor and co-activator complexes
(Fig. 1, `nucleus'). In the
absence of Notch signaling, CSL associates with transcriptional co-repressors
that actively keep target gene expression switched off
(Kao et al., 1998
). Following
Notch activation, the CSL co-repressor complex is replaced by a co-activator
complex coordinated by Notchintra. Active repression of targets in
the absence of Notch signaling allows cells to tightly control signaling
outputs (see Box 4 for unexpected consequences of this), and this dual mode of
regulation is now understood to be a common feature of most of the major
signaling cascades (reviewed by Barolo and
Posakony, 2002
).
Box 2. Notch proteolytic processing
Following the suggestion that Notch is cleaved during Notch signaling in
the early 1990s, the search for the `Notch-ase' was on. Notch proteolysis
turned out to be more complicated than anticipated, and involves successive
cleavage events termed S1, S2 and S3 (Fig.
1, note that S1 is not shown) (reviewed by
Fortini, 2002
|
Although engagement of the Notchintra/CSL activator complex is
normally necessary for a target gene to respond to Notch signaling, it is not
always sufficient. Indeed, no Notch target gene is expressed in every location
where Notch itself is activated. This specificity is due to co-regulation of
Notch target genes by other transcription factors and/or signaling pathways
(reviewed by Bray and Furriols,
2001). For example, cone cell-specific expression of pax2
(sv - FlyBase) during Drosophila eye development is achieved
through coordinated regulation by at least three inputs - Notch signaling, EGF
receptor signaling and Lozenge (Flores et
al., 2000
). Combinatorial regulation allows for a transcriptional
response that is appropriate for each different developmental setting (see
also Box 4 for consequences of complex gene regulation).
Regulation of development by Notch signaling
Notch mutant fly embryos are so strongly affected that Donald
Poulson, who pioneered the use of mutants to study fly development, was
compelled to write that `All in all, a kind of hopeless monster is produced
which can not develop beyond the embryonic stage'
(Poulson, 1945). We now know
that Notch is likely to be involved in the development of most tissues in
species throughout the animal kingdom, with myriad effects on cell fate
specification, proliferation and cell death
(Table 2). The following
examples are a brief glimpse into the repertoire of Notch, and illustrate some
different types of Notch-regulated patterning events.
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|
Many proteins that mediate neural repression in Drosophila are
encoded by the Enhancer of split Complex [E(spl)-C]. This
genomic region contains multiple genes that are directly turned on by Notch
signaling via CSL-binding sites in their promoters
(Bailey and Posakony, 1995;
Lecourtois and Schweisguth,
1995
), including several genes that encode related bHLH repressor
proteins. Forced expression of E(spl)bHLH repressors is sufficient to inhibit
neural development (Nakao and
Campos-Ortega, 1996
), possibly by directly inhibiting the
expression of bHLH proneural activators
(Heitzler et al., 1996
).
The same E(spl)bHLH repressors are deployed in other settings where Notch
signaling restricts the number of progenitor cells during Drosophila
development, including those of the visceral and somatic musculature, midgut
and intestine, heart and a host of other internal organs
(Hartenstein et al., 1992).
Notch signaling in vertebrates also represses neurogenesis and myogenesis
(Fig. 2E,F and
Table 2) via homologous
Hairy/E(spl)-related bHLH repressors known as HES (mammal), HER (fish) or ESR
(frog) proteins (Chitnis et al.,
1995
) (reviewed by
Artavanis-Tsakonas et al.,
1999
). Activation of bHLH repressors by Notch signaling is
therefore a general strategy for preventing equipotent cells from all
acquiring the same fate, a role sometimes referred to as `inhibitory Notch
signaling'.
Notch signaling specifies cell fates and creates boundaries
A second general role of Notch is to promote the development of a given
cell type or body region, often by inducing the expression of positively
acting regulatory molecules. In many of these cases, Notch signaling creates a
new cell type as a result of cell-cell interactions at the boundary between
distinct cell populations (Fig.
3A,B). This is sometimes referred to as `inductive' Notch
signaling, and contrasts with the `inhibitory' role of Notch where Notch
signaling represses a given cell fate among equipotent cells.
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Notch signaling also works at boundaries during vertebrate somitogenesis.
The segmented vertebrate body plan is founded upon regularly spaced blocks of
mesoderm known as somites. Somites split off progressively from the presomitic
mesoderm, a process driven by periodic oscillations in gene expression that
are called the segmentation `clock'. Notch signaling appears to be central to
the segmentation clock, as the expression of many Notch pathway components
oscillates within the presomitic mesoderm, and mutation of members of the
Notch pathway causes defects in clock oscillation and segmentation
(Fig. 3F,G) (Conlon et al., 1995;
Palmeirim et al., 1997
)
(reviewed by Bessho and Kageyama,
2003
). Oscillating gene expression involves an auto-repressive
activity of the Notch-activated bHLH repressors Hes1 and Hes7, which turn
their own expression off. As these repressor proteins are short lived, their
rapid degradation permits a new cycle of Hes1/7 transcription to
begin (reviewed by Bessho and Kageyama,
2003
).
It remains to be fully understood, though, how the segmentation clock
physically leads to somitogenesis, and whether or not Notch/CSL or Hes
proteins directly regulate any genes that mediate somite partitioning. More
generally, there are many `inductive' Notch-regulated developmental processes,
in which Notch signaling promotes rather than represses a cell type or
behavior, for which the relevant target genes remain to be identified. For
example, it is not well understood how Notch promotes germline proliferation
in C. elegans (Berry et al.,
1997) (Fig. 3H,I)
or specifies cell fates such as mammalian astrocytes, fly glia and early worm
blastomeres (Table 2). Although
bHLH repressors are expressed in some `Notch-inductive' settings, most of the
well-characterized examples also involve the direct activation of genes that
encode positively acting transcriptional regulators or proteins specific to
terminally differentiated cells. Whether this is generally true or not will be
revealed by a more detailed understanding of genes directly regulated by
Notchintra/CSL during normal development.
Giving direction to Notch signaling
As we have now seen, the major biological role of Notch signaling is to
control the developmental fates of cells and to make cells different from one
another. Therefore, cells become distinguished from one another according to
whether they predominantly send or receive Notch signals. In some cases, this
is easily explained by the exclusive distribution of ligand and receptor. For
example, during C. elegans gonadal development, the somatic distal
tip cell signals to adjacent germline cells to induce their division, which
generates the pool of germline cells. The directionality of signaling is due
to the fact that the distal tip cell expresses only the ligand LAG-2, while
the germline cells express only the Notch receptor GLP-1
(Henderson et al., 1994).
Notch ligands often show spatially patterned expression, so this is a general
focal point for controlling Notch signaling. However, there are many
situations where all of the cells involved in Notch signaling express both
ligand and receptor. How is signaling made directional in these cases?
Feedback regulation in Notch signaling
Notch signaling sometimes shows a remarkable ability to amplify small
differences in the signaling capacities of different cells. One tactic is for
signaling to regulate receptor and/or ligand transcription. In this way, the
degree to which a cell activates Notch signaling has a dynamic effect on how
well it sends and/or responds to Notch signals in return.
A clear example of this occurs during the anchor cell/ventral uterine cell
(AC/VU) decision in C. elegans gonadal development. Although the
destiny of almost all nematode cells is predetermined by lineage, AC and VU
acquire their identity through a Notch-mediated discussion between two cells,
referred to as Z1.ppp and Z4.aaa. Initially, LIN-12 (Notch) and LAG-2 (ligand)
are expressed by both cells, and they engage in `mutual' bi-directional Notch
signaling. However, random fluctuation in expression of LIN-12 and LAG-2 is
amplified by positive feedback; activation of LIN-12 promotes its own
expression and inhibits the expression of LAG-2 by the cell. In the end, one
cell expresses only the ligand and differentiates as AC, while the other cell
expresses only receptor and turns into VU
(Wilkinson et al., 1994;
Christensen et al., 1996
). A
directional signaling situation like this is sometimes called `lateral'
signaling.
Similar `mutual' to `lateral' Notch signaling is seen during the selection
of Drosophila neural precursors from groups of equipotent proneural
cluster cells discussed earlier (Fig.
2A), a process known to be very sensitive to the levels of ligand
and receptor in each individual cell
(Heitzler and Simpson, 1991).
A proposed mechanism for Notch-mediated regulation of ligand incorporated the
finding that the expression of Delta can be activated by proneural
proteins, which are, in turn, inhibited by Notch-activated bHLH repressors
(Heitzler et al., 1996
).
However, this regulatory chain does not fully explain how signaling becomes
directional, as increased levels of proneural proteins in neural precursors
and decreased levels of proneural proteins in the inhibited cells are not well
correlated with changes in Delta or Notch levels during normal development
(Parks et al., 1997
). Thus,
post-transcriptional mechanisms to amplify differences in Delta-Notch
signaling must also exist, some of which are discussed in the next
section.
Modulating ligand and receptor activity
A second way to influence Notch signaling among cells that co-express
ligand and receptor involves post-translational modifications. Two molecules
that target the Delta ligand are Neuralized and Mindbomb. Although they are
not related to one another structurally, both are RING-type E3 ubiquitin
ligases that directly ubiquitinate Delta and cause it to be internalized from
the plasma membrane. Recent studies show that the effect of Neuralized and
Mindbomb is actually to increase the ability of Delta to activate Notch
signaling in neighboring cells (Itoh et
al., 2003) (reviewed by Le
Borgne and Schweisguth, 2003
). One way in which this might work is
if the extracellular domain of Notch is co-internalized with Delta into the
Delta-expressing cell, which might facilitate the `S2' cleavage of Notch in
the Notch expressing cell (Fig.
1). The expression of these ubiquitin ligases is initiated in a
subset of Notch-dependent processes, including neurogenesis, and may be
responsible for making Notch signaling directional during the neural/epidermal
fate decision.
Notch activity is regulated by sequential glycosylation of particular EGF
repeats (reviewed by Schweisguth,
2004). Notch modification by the glycosyltransferase Fringe has
complex effects. Fringe inhibits the ability of Notch to be activated by
Serrate- and Jagged-type ligands, but stimulates the response of Notch to
Delta-type ligands (Panin et al.,
1997
). In vitro data suggest that Fringe enhances Notch-Delta
binding and decreases Notch-Serrate binding. Fringe is often deployed in a
spatially restricted pattern to position or create directional Notch signaling
during cell fate-inductive events. Some examples of this occur during
development of the fly wing margin, at the dorsoventral boundary of the fly
eye, at the dorsoventral limb borders of vertebrate limbs and in developing
vertebrate somites (reviewed by Irvine,
1999
).
Inherited factors bias inhibitory Notch signaling
A special type of directional inhibitory Notch signaling occurs during many
instances of asymmetric cell divisions
(Fig. 4A). In this situation,
although both sister cells are capable of sending and receiving Notch signals,
directionality is imposed by the asymmetric segregation of factors that
influence Notch signaling. Such factors localize to a crescent centered at one
end of the mitotic spindle in the mother cell
(Fig. 4B).
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Aberrant Notch signaling in human disease
Given the profound and widespread roles of Notch signaling across a range
of tissues, it is perhaps no surprise that deviant Notch signaling underlies
some human diseases. Consistent with the roles of Notch signaling in
development and neural behavior, relevant heriditary conditions include
Alagille syndrome (where mutations in the Notch ligand JAG1 affect
the development of many organs, including that of the liver, skeleton, heart
and eye) (Li et al., 1997;
Oda et al., 1997
), certain
forms of spondylocostal dysostosis (where mutations in the ligand
DLL3 result in rib fusions and trunk dwarfism)
(Bulman et al., 2000
) and
cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL) (where mutations in the extracellular EGF
repeats of NOTCH3 predispose individuals to dementia, migraines and
strokes) (Joutel et al.,
1996
). In addition, a mild decrease in Notch signaling in mice
causes specific defects in spatial learning and memory, which might make Notch
a more general culprit in cognitive deficits
(Costa et al., 2003
).
Aberrant Notch signaling is also intimately involved in several human
cancers. This was first demonstrated in a recurrent t(7;9) translocation that
is associated with certain pre-T cell acute lymphoblastic leukemias (T-ALL)
(Ellisen et al., 1991). This
chromosomal rearrangement results in constitutive Notch activity in T cells.
Conversely, cells that are mutant for Notch1 form skin and corneal
tumors in mice, indicating that Notch also suppresses tumorigenesis
(Nicolas et al., 2003
). Many
other human and murine cancers, including certain neuroblastomas, and mammary,
skin, cervical and prostate cancers, are correlated with alterations in
expression of Notch proteins and/or ligands. Although causal relationships in
many cases await better characterization, these observations suggest broad
roles for Notch dysfunction in cellular transformation.
The CSL transcription factor is a particular victim of viruses that
redirect CSL function towards their own ends. Multiple proteins from
Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), and
adenovirus type 5 bind CSL directly and modulate CSL-dependent transcription
of both viral and host target genes in a Notch-independent fashion (reviewed
by Allenspach et al., 2002). A
majority of humans are latently infected with EBV and adenovirus, but, as is
the case for KSHV, initial infection is usually asymptomatic. A serious
problem arises in immunocompromised individuals, though, where opportunistic
behavior of EBV and KSHV causes oncogenic transformation and malignancy.
The molecular elucidation of these diseases is now the basis of diagnostic tools. However, it is hoped that knowledge of the mechanism of Notch signaling will be relevant for therapeutic design. This hope remains to be realized, but one can imagine that conditions that arise from Notch pathway gain-of-function might be alleviated by small molecule antagonists of genetic inhibitors of Notch processing/Notchintra-co-activator function, while conditions that arise from Notch pathway loss-of-function might be treated with targeted delivery of soluble Notch ligands or other strategies that either locally activate Notch activity or suppress CSL co-repressor activity. A variety of relevant mouse disease models are now available to help test these strategies. Of course, given the very general functions of the Notch pathway, minimization of collateral or non-specific effects will be necessary to make such therapies clinically useful.
Concluding remarks
A clear theme of developmental and evolutionary biology is that nature is
frugal: useful proteins and signaling pathways are reused in diverse settings.
Notch signaling is an example of a particularly successful signaling cascade
that is used repeatedly throughout the development of all metazoan organisms.
Many Notch-mediated affairs are highly analogous; for example, Notch signaling
mediates the inhibition of many different cell fates through the same bHLH
repressor proteins. However, the redeployment of this pathway during evolution
has resulted in diverse outcomes to Notch activation in different situations.
Depending on the setting, Notch can inhibit, delay or induce differentiation,
and can variously promote apoptosis, cell division or a static state
(Table 2). Things become more
complicated when one considers how signaling pathways interact with one
another. For example, Notch signaling and EGF receptor signaling can work in
parallel or in series to regulate a given process, and can either cooperate or
antagonize each other during transcriptional regulation of a given target.
Notch signaling is also influenced by a great number of other factors in
specific settings, only some of which have been addressed in this primer
(reviewed by Greenwald, 1998;
Schweisguth, 2004
). All of
these considerations mean that although one can be guided by previous studies,
it is imperative to evaluate each new example of Notch signaling
carefully.
Given the pervasive use of the Notch pathway in animal development, how was this signaling cascade originally assembled during evolution? Although only metazoans are known to use Notch signaling, certain `prospective' components of the Notch pathway are found in other types of eukaryotes. A striking example is the definitive existence of CSL homologs in some fungi. If these species never had a Notch pathway, they may shed light on ancestral functions of CSL transcription factors. Will they be found to be transcriptional activators or repressors, or both? And are there any species in which both Notch and CSL are present, but are not associated in a common signaling process? It will be a great future challenge to understand when and how functional connections arose between components of a presumptive Notch pathway during evolution.
ACKNOWLEDGMENTS
Elise Lamar, Jose F. de Celis, Tim Schedl, Clarissa Henry, Fabrice Roegiers and Scott Barolo graciously contributed images.
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