of the Notch signaling pathway could induce S-phase
entry, resulting in disc overgrowth. Notch acts in part by
inhibiting the Drosophila retinoblastoma homolog Rbf,
which normally functions to inhibit the S-phase-specific
E2F transcription factor. Notch is also required for ex-
pression of Cyclin A; in addition, Notch may regulate a
third, unknown factor to drive S-phase entry because
coexpression of both E2F and Cyclin A did not rescue
S phase in Notch mutant clones (Baonza and Freeman,
2005). Once cells transit through S phase into G2, they
arrest until a further signal from differentiating neurons,
dependent on the epidermal growth factor receptor,
drives entry into mitosis (Baker and Yu, 2001).
What are the targets of Hedgehog and Dpp that me-
diate cell-cycle synchronization and arrest within the
morphogenetic furrow? One likely target is String, the
Drosophila homolog of the mitotic inducer Cdc25.
String expression ahead of the furrow is required to
drive cells through mitosis and into G1 (Heberlein et
al., 1995; Mozer and Easwarachandran, 1999). Another
candidate is Roughex, a gene required to inhibit Cyclin
A-dependent kinase activity in the morphogenetic fur-
row. In the absence of Roughex, all cells in the furrow
enter S phase prematurely. Roughex is expressed in the
morphogenetic furrow, consistent with induction by
Hedgehog, and the phenotype of roughex mutations is
enhanced by mutations in hedgehog (Thomas et al.,
1997). Direct cell-cycle targets of Dpp signaling have
yet to be identified.
Other genes downstream of Hedgehog and Dpp
likely include the G1 cyclin Cyclin D and the bHLH tran-
scription factors Hairy, Atonal, and Daughterless,
among others, whose expression is manifested as dra-
matic stripes across the disc. Hedgehog and Dpp also
induce expression of the Notch ligand, Delta, and this
expression is required for Notch activity in regulating
(Baonza and Freeman, 2005). The integration of these
complex signals results in the formation of regularly
spaced groups of cells across the length of the furrow
that are committed to differentiate into neurons. That
cell-cycle entry behind the morphogenetic furrow de-
pends on these same regulatory signals ensures that
precursor cells will be generated at the right time and
place and in the right numbers to pattern the adult eye.
Although it is likely that the highly structured nature of
the Drosophila compound eye requires an unusually
stringent control, it is likely that proliferation and
patterning will be linked by common regulatory signals
in other organisms as well.
Barbara J. Thomas
Center for Cancer Research
National Cancer Institute
National Institutes of Health
9000 Rockville Pike
Bethesda, Maryland 20892
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Developmental Cell, Vol. 8, April, 2005, Copyright ©2005 by Elsevier Inc. DOI 10.1016/j.devcel.2005.03.005
living beings to have caused a profound change in the
composition of Earth’s atmosphere. Over 2.2 billion
years ago, oxygen became abundant as a result of
“early” life, causing radical changes to the ecosystem
with consequences potentially far more harmful than
today’s “green-house effect.” This accumulation of oxy-
gen caused extinction of most existing life forms, de-
fenseless against oxidation-mediated toxicity. Eventu-
ally new life forms emerged and flourished in the new
environment. This aerobic life possessed effective anti-
oxidant mechanisms and even began exploiting oxygen
and its derivates—so-called reactive oxygen species
(ROS)—for production of energy and signal transduc-
One pathway that harnessed the potent reactivity of
Oxygen JNKies: Phosphatases
Overdose on ROS
Proinflammatory cytokine TNF? triggers cell death by
inducing reactive oxygen species (ROS). These then
inflict cytotoxicity through downstream activation of
the JNK MAPK cascade. Yet the mechanisms by which
ROS trigger JNK signaling have remained elusive. In
a recent issue of Cell, Kamata et al. now provide one
It might be surprising to know that we are not the first