Development 137 (24)
IN THIS ISSUE
Pak1-ing a punch in lumen
formation
The generation and maintenance of correct
lumen size and shape is essential for the function
of tubular organs. Now, Monn Monn Myat and
co-workers report that p21-activated kinase (Pak1) plays a novel role during
lumen formation in Drosophila embryonic salivary glands (see p. 4177). The
researchers show that Pak1 regulates the size and elongation of the apical
domain of individual epithelial cells in the developing gland by decreasing and
increasing E-cadherin levels at adherens junctions and basolateral membranes,
respectively. Pak1 mediates these effects, they report, through Rab5- and
Dynamin-dependent endocytosis of E-cadherin. Moreover, constitutively active
Pak1 induces the formation of multiple intercellular lumens in the gland, an
effect that is dependent on Rab5 and Dynamin, and on the Pak1 substrate
Merlin. Together, these results identify a crucial role for Pak1 and E-cadherin
endocytosis in lumen size and shape determination in fly salivary glands, and
highlight a mechanism for multiple lumen formation, a process that occurs in
pathological conditions such as breast ductal carcinoma in situ.
Ongoing Phox2 locks in neuronal
differentiation
During neuronal differentiation, expression of the
transcription factors that determine neuronal identity often
continues after their downstream genetic program has
been launched. Is this continued expression required for
neuronal differentiation? On p. 4211, Jean-François Brunet and colleagues
address this question by inactivating the paired-like homeobox genes Phox2a
and Phox2b, which specify several classes of visceral neurons, after the
developmental timepoint at which they act to initiate visceral neuron
differentiation. They report that ongoing Phox2b expression is required in
branchiomotor and visceromotor neuronal precursors after their initial
specification to maintain their molecular signature, migration pattern and
cellular differentiation. Similarly, maintenance of noradrenergic neuron
differentiation during embryogenesis requires the ongoing expression of
Phox2b in sympathetic ganglia and of Phox2a in the main noradrenergic centre
of the developing brain. Thus, neuronal differentiation does not always unfold
as a transcriptional ‘cascade’ in which downstream events are irreversibly
triggered by an upstream regulator. Instead, as seen here, it sometimes requires
continuous input from so-called ‘terminal selector genes’.
Shh signalling out-Foxed by
cilia
Leaves send mobile signals for size
Organ size in plants and animals is tightly controlled,
and partly determined, by cell size and number. Plant
leaves, for example, exhibit compensation, in which
defective cell proliferation triggers increased postmitotic
cell expansion. Now, Hirokazu Tsukaya and colleagues
(p. 4221) identify two novel pathways coordinating cell proliferation and
expansion in Arabidopsis leaves. Two Arabidopsis mutants, the loss-of-function
ANGUSTIFOLIA3 (AN3, a transcriptional co-activator) mutant and the
overexpressor KIP-RELATED PROTEIN2 (KRP2, a cyclin-dependent kinase
inhibitor) mutant show compensation: in an3 mutant leaves, cell numbers
decrease by ~70%, whereas cell size increases by 50%. Using the Cre/lox
system, the authors generated leaves chimeric for AN3 and KRP2 expression,
and investigated whether compensation occurs in a cell-autonomous or noncell-autonomous manner. An3-dependent compensation, they report, is
indeed non-cell-autonomous and occurs via an intercellular signal restricted to
one half of leaves. Conversely, compensation caused by KRP2 overexpression
occurs cell-autonomously, possibly via a mitotic cell cycling defect. Future work
should shed more light on these events and identify the transmitted signal.
Hippo links growth control to
tissue homeostasis
Both tissue repair and tissue homeostasis require
stem cells that proliferate to replenish lost cells,
but the way in which adult stem cells respond to
damage and switch between homeostatic and rapid proliferative states is not
well understood. In the Drosophila midgut, intestinal stem cells (ISCs) maintain
homeostasis, and, in response to damage, can proliferate rapidly following
activation of the Jak/Stat pathway. In this issue, two papers demonstrate that
Drosophila ISC proliferation, and hence intestinal regeneration, are regulated
by the Hippo (Hpo) tumour suppressor pathway, providing an exciting new link
between growth control and stem cell proliferation.
On p. 4147, Nicolas Tapon and colleagues examine the effects of Hpo
pathway inactivation in the midgut by overexpressing Yorkie (Yki), a progrowth target that is usually repressed by the Hpo pathway. They report that
Yki overexpression in differentiated cells increases
ISC proliferation non-cell-autonomously without
affecting differentiation, and induces the
expression of the Jak/Stat pathway ligand
Unpaired. The authors also observe that Yki target
genes are induced by bacterial infection, and
suggest that the Hpo pathway acts to sense cellular
stress within the midgut. Finally, using RNAi, they show that Yki is also required
within ISCs to drive proliferation in response to bacterial-induced tissue stress.
Based on their findings, they propose that the Hpo pathway is a mediator of
the Drosophila midgut regenerative response.
In a second, related paper, Norbert Perrimon and co-workers (p. 4135)
demonstrate that Yki overexpression in ISCs induces proliferation cellautonomously, whereas Yki loss has no effect on ISCs during normal
homeostasis. They also show that Yki activity is required in ISCs to mediate the
proliferative response to tissue damage, and propose that this effect is elicited
by downstream targets that are involved in proliferation and survival.
Importantly, they report that, prior to tissue damage, Yki is also repressed by
the atypical cadherins Fat and Dachsous, which are upstream components of
the Hpo pathway. From their findings, the researchers propose that Yki is
inactive under normal homeostasis but becomes activated to induce ISC
proliferation when cell-contact cues, and thus Hpo signal transduction, are
disrupted by tissue injury.
DEVELOPMENT
Sonic hedgehog (Shh) signalling controls cellular
differentiation in the neural tube by regulating a
poorly defined gene regulatory network. To
better understand this network, James Briscoe and colleagues have
undertaken a genome-wide expression screen in chick neural tube and, on
p. 4271, they identify the forkhead transcription factor Foxj1 as an Shh target
gene in this tissue. Foxj1, they report, is expressed in the chick and mouse
neural tube in cells that constitute the floor plate (FP), a neural tube organising
centre. Foxj1 expression is associated with the formation of long motile cilia in
several cell types and, consistent with this, the authors show that chick and
mouse FP cells produce primary cilia longer than those produced elsewhere in
the neural tube. Finally, they show that Foxj1 expression in the neural tube
attenuates Shh signal transduction by altering cilia structure and modifying the
intracellular localisation of the Gli proteins that mediate Shh signalling.
Together, these data reveal a novel cilia-dependent mechanism that modulates
cellular responses to Shh signalling.