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Department of Physics, Worcester
Polytechnic Institute, 100 Institute Road,
Worcester, MA 01609, USA.
Notch Signaling: A Role in Sleep
The molecular pathways regulating sleep remain poorly understood. Studies in
this issue demonstrate a role for Notch signaling in sleep regulation as well as
stress response in both Caenorhabditis elegans and Drosophila.
Mark N. Wu1and David M. Raizen2,*
It has become clear in recent years
that signaling pathways used for
development also play roles in
regulation of nervous system
physiology. Notch signaling, which
has classically been studied in cell
fate specification during development
, is increasingly recognized to play
important roles in the adult nervous
system [2–5]. Ligand activation of
NOTCH causes the cleavage of the
translocates to the nucleus to regulate
gene transcription, thus impacting
development or behavior . Two
Biology [7,8], reveal a role for this key
signaling pathway in the regulation of
sleep and sleep-like states in both
The discovery of a role for Notch
signaling in the regulation of C. elegans
quiescence and sleep-like behavior
began with an unexpected
observation. The authors had been
is a founding member of a family of
domains . They noticed that
overexpression of OSM-11 causes
adult animals to stop moving and
feeding. This quiescence induced by
OSM-11 is dependent on lin-12 and
glp-1, the two C. elegans genes
encoding Notch receptors.
Behavioral quiescence under
occurs only during lethargus, a stage
with sleep-like behavioral features that
is associated with each ofthe fourlarval
molts . Therefore, observing the
induction of adult quiescence by
OSM-11 overexpression and Notch
signaling led Singh and colleagues 
to test for a role of this signaling
pathway in lethargus behavior.
The behavior of OSM-11
overexpressing animals is similar to
that of worms in lethargus in that they
both have elevated arousal thresholds,
a property seen in sleep. Further,
OSM-11-induced quiescence is
dependent on the genes egl-4, deg-3,
and ceh-17, all of which regulate
lethargus. The egl-4 gene encodes
a cGMP-dependent protein kinase
required fornormal molting quiescence
and sleep-like behavior , whereas
deg-3 and ceh-17 are required for the
function of ALA, a single interneuron
that is required for normal expression
of lethargus quiescence . Loss of
OSM-11 in combination with loss of
another DOS domain protein called
OSM-7 results in severely reduced
molting quiescence and increased
responsiveness during the normally
sleep-like lethargus period . These
experiments thus demonstrate that
Notch signaling and, in particular,
DOS domain Notch ligand signaling,
promotes sleep-like behavior during
However, this simple model
becomes more complicated when
considering the phenotypes of osm-11
and osm-7 single mutants and of single
mutants in each of the two worm
NOTCH receptors. Surprisingly, these
mutants show increased (not
decreased) total lethargus quiescence.
But the authors also show that every
genetic manipulation that reduces
Notch signaling results in a lowering of
during lethargus. Their careful analysis
underscores the importance of
considering not only the quantity but
also the quality of sleep in invertebrate
The second paper published in
this issue of Current Biology examines
the role of Notch signaling in sleep
regulation in Drosophila melanogaster
. The evidence that Drosophila
sleep is fundamentally similar to
mammalian sleep is extensive and
includes genetic, molecular, and
pharmacological observations .
Seugnet and colleagues  focus their
analysis on the phenomenon of
increased sleep (‘sleep rebound’)
following sleep deprivation. Sleep
rebound is thought to reflect increased
sleep pressure driven by a sleep
Seugnet and colleagues begin with
the observation that the transcription
factor bunched, which has been shown
to negatively regulate Notch signaling
, is upregulated following sleep
deprivation. They build upon this initial
observation, exploring the role and
cellular basis of Notch signaling in
homeostatic regulation of sleep.
They show that overexpression of
the NOTCH ligand DELTA in
mushroom bodies, a structure
implicated in learning/memory as
well as sleep regulation [14,15],
reduces sleep rebound. Similarly,
a Notch gain-of-function allele also
exhibits reduced sleep rebound.
Taken together, these data suggest
that sleep deprivation normally
suppresses Notch signaling (by
upregulating bunched), and that this
reduction of Notch signaling allows
for the expression of sleep rebound.
The function of sleep is unknown
but one popular theory posits that
sleep modulates synaptic plasticity
and learning and memory . In
previous work, the authors showed
that sleep-deprived flies are defective
in a specific associative learning task
[17,18]. The authors show that
increasing Notch signaling (by either
overexpressing DELTA in mushroom
bodies or by using a gain-of-function
allele of Notch) can rescue the
detrimental effects of sleep deprivation
One interpretation of these data is
that the reduced Notch signaling
the learning impairment seen after
sleep deprivation. An alternative trivial
explanation for these results is that the
learning impairment results from an
overall reduction of arousal and that
enhancing Notch signaling simply
promotes arousal. However, the
authors argue in previous studies that
sleepiness does not impair learning
performance in this assay [17,18].
Where do NOTCH and their ligands
act to regulate sleep? The authors
in glia, while DELTA is expressed in
neurons. They then find that selective
overexpression of the NOTCH
intracellular domain in glia results in
reduced sleep rebound, as well as
a rescue of the adverse effects of sleep
deprivation on learning. These data
suggest that glia play a role in both
sleep rebound and learning.
Interestingly, a recent study of mice in
which gliotransmission was blocked
came to a similar conclusion regarding
the role of glia .
The finding that reduced Notch
signaling is associated with learning
impairment following sleep
deprivation, while increased Notch
signaling can rescue this defect, raises
the question of whether Notch
signaling promotes the synaptic
plasticity underlying learning and
memory. Intriguingly, two recent
publications demonstrate that Notch
signaling is increased following
neuronal activity [2,20] and, in mice, is
necessary for synaptic plasticity .
How do we reconcile the findings
from these two papers in this issue [7,8]
regarding Notch and sleep? In worms,
Notch promotes sleep, whereas in flies,
Notch inhibits the homeostatic sleep
response. While the effects on sleep
regulation may be different, an
observation made in both systems is
that Notch signaling is reduced in
flies, mechanical or oxidative stress
induces the Notch negative regulator
bunched, whereas in worms, osmotic
stress represses the secretion of the
Notch positive regulator OSM-11.
Further, loss of osm-11 mimics the
physiological effects of adaptation to
osmotic stress [7,8]. Therefore, it is
possible that Notch has an ancient
role in the response to environmental
stressors, including sleep deprivation,
but that the behavioral consequences
and worms. In addition,considering the
growing evidence that Notch signaling
plays a role in synaptic plasticity, it is
tempting to speculate that Notch may
be one of the molecular signals
accounting for the effects of sleep and
stress on synaptic plasticity. It will be
important to see if in mammals sleep is
also regulated by Notch signaling and if
this pathway plays a role in the plastic
changes promoted by sleep.
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Fortini, M.E. (1995). Notch signaling. Science
2. Alberi, L., Liu, S., Wang, Y., Badie, R.,
Smith-Hicks, C., Wu, J., Pierfelice, T.J.,
Abazyan, B., Mattson, M.P., Kuhl, D., et al.
(2011). Activity-induced notch signaling in
neurons requires arc/arg3.1 and is essential
for synaptic plasticity in hippocampal
networks. Neuron 69, 437–444.
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Belle, J.S., and Andres, A.J. (2004). Notch is
required for long-term memory in Drosophila.
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Woerden, L.H., Saiepour, M.H., Nakazawa, K.,
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Tucey, T., Dionne, H.M., Walsh, M.B.,
Beaumont, E.K., et al. (2011). C. elegans Notch
signaling regulates adult chemosensory
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8. Seugnet, L., Suzuki, Y., Merlin, G.,
Gottschalk, L., Duntley, S.P., and Shaw, P.J.
(2011). Notch signaling modulates sleep
homeostasis and learning after sleep
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Maycock, M., You, Y., Sundaram, M.V., and
Pack, A.I. (2008). Lethargus is a C. elegans
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1Department of Neurology, Johns Hopkins
University, Baltimore, MD 21287, USA.
2Department of Neurology, University
of Pennsylvania School of Medicine,
Philadelphia, PA 19014, USA.
Evolutionary Genetics: Evolution with
Evolution has no foresight, but produces ad hoc solutions by tinkering with
available variation. A new study demonstrates how evolution nevertheless
prepares organisms for the future by increasing their evolvability.
Merijn L.M. Salverda
and J. Arjan G.M. de Visser*
Evolution produces ad hoc solutions
for present problems rather than
perfect designs for future needs.
Evolution cannot follow
a preconceived plan, because it lacks
foresight. In the words of Francois
Jacob: ‘‘evolution works like a tinkerer,
Current Biology Vol 21 No 10