IN THIS ISSUE
p63 function: a hairy tale
The transcription factor p63 is required for the
development of the stratified skin epithelium and of
hair follicles. But, although its role in early skin
development is well understood, little is known
about how p63 directs hair follicle morphogenesis.
Now, Satrajit Sinha and co-workers report that Np63, the major p63
isoform expressed in skin, suppresses hair follicle differentiation in mice (see
p. 1431). Np63, they report, is expressed in the developing hair placode but
its expression is restricted to the outer root sheath (ORS), matrix cells and stem
cells of the hair follicle bulge in mature hair. They show that targeted Np63
overexpression in the ORS leads to dramatic defects in hair follicle development
and hair cycling, and causes follicular keratinocytes to adopt an interfollicular
cell fate. Global profiling and other experiments suggest that the loss of crucial
signalling molecules, including Wnt/-catenin, causes the hair follicle defects.
Together, these results reveal the in vivo function of a specific p63 isoform and
provide new insights into hair development.
Hox-free anteroposterior
patterning
In vertebrates, Hox genes play a key role in
specifying positional identity along the
anteroposterior axis. However, little is known
about the function of these conserved genes in invertebrates other than in
insects and nematodes. Now, surprisingly, Hidetoshi Saiga and colleagues
report that Hox genes have limited functions during the larval development of
the protochordate Ciona intestinalis (see p. 1505). In C. intestinalis, seven Hox
genes are expressed during embryogenesis. Using antisense morpholino
oligonucleotides directed against each of these genes, the researchers show
that Ci-Hox12 plays an important role in tail development by maintaining the
expression of Ci-Fgf8/17/18 and Ci-Wnt5 in the tail tip epidermis, and that CiHox10 is involved in the development of GABAergic neurons in the dorsal
visceral ganglion. Unexpectedly, however, knockdown of Ci-Hox1, 2, 3, 4 or 5
causes no consistent morphological defects. Thus, the contribution of Hox
genes to the patterning of the larval anteroposterior axis in C. intestinalis might
be very limited, a result that challenges the accepted paradigm for Hox gene
function.
Setting a boundary for Notch’s
role in somitogenesis
What role does Notch signalling play in segment
boundary formation during somitogenesis? Some
studies suggest that segment boundaries form where
boundaries of Mesp2 expression coincide with boundaries of on/off Notch
expression (where cells with an activated Notch pathway interface with cells in
which it is off). However, other studies suggest that segment boundaries form
correctly even when there are no Notch on/off boundaries. On p. 1515,
Yumiko Saga and co-workers resolve this long-standing controversy by
examining somitogenesis in a transgenic mouse that lacks Notch on/off
boundaries in the anterior PSM but retains Notch signal oscillation in the
posterior PSM (Notch signal oscillation is a component of the ‘segmentation
clock’ that controls the timing of somitogenesis). Segmented somites are
continuously generated in this mouse, they report, and, surprisingly, rostralcaudal patterning within the somites is normal. Given these results, the
researchers propose that the oscillation of Notch activation, but not its
boundary, is both required and sufficient to establish the Mesp2 expression
pattern needed for normal somitogenesis.
Developing the tumour
suppressor functions of VHL
von Hippel-Lindau disease is a rare, familial
genetic disease in which benign and malignant
tumours grow in the kidneys and in the
vasculature associated with various parts of the nervous system (in particular,
the retina). The gene mutated in this disease – VHL – is a conserved E3
ubiquitin ligase that regulates angiogenesis and glycolysis by destabilising
hypoxia-inducible transcription factor (HIF) under normoxic conditions.
Oxygen sensing thus represents the canonical tumour suppressor function of
VHL. However, in this issue, two papers provide information on the
developmental roles of VHL that suggest it has other tumour suppressor
functions as well.
On p. 1493, Tien Hsu, Giuseppe Gargiulo and colleagues report that VHL
regulates epithelial morphogenesis during Drosophila development. The
researchers generate the first genomic VHL Drosophila mutant and examine
epithelial morphogenesis in the follicle cells of the egg chamber in this
mutant. They show that VHL regulates the apical localisation of atypical
protein kinase C (aPKC) and that this function of VHL is mediated, at least
in part, by the action of VHL on microtubule stability. Without VHL function,
they report, microtubules and aPKC are destabilised, which results in
epithelial defects. Because loss of epithelial integrity is a crucial step in
tumorigenesis, these results suggest that a potential additional tumour
suppressor function for VHL is regulation of epithelial morphogenesis.
On p. 1563, Toshio Suda, Hideyuki Okano and colleagues report that VHL
regulates the fetal to adult retinal circulatory system transition in mice. After
birth, the hyaloid vessels that circulate blood in the
neonatal retina are replaced by retinal vessels in a
process that is mediated by macrophages. But could
the dramatic change in the oxygen environment
that occurs at birth also be involved in this
transition? To find out, the researchers generate
retina-specific VHL conditional-knockout mice and
show that the fetal to adult retinal circulatory system transition is arrested
in these animals. This arrest can be rescued by local VEGF inhibition or by
genetic inhibition of HIF-1. Thus, VHL-mediated oxygen-sensing
mechanisms help to regulate the development of the adult circulatory
system in the retina, a finding that might explain why retinal angiomas are
a common characteristic of VHL disease.
Blocking polygamy at the plasma
membrane
A newly formed zygote undergoes rapid changes that
prevent other gametes from fusing with it. In many
organisms, changes to the zygote plasma membrane after
fertilization hold the key to this block, but what are these
changes? William Snell and colleagues on p. 1473 now
provide the first molecular explanation, in any organism, for a mechanism
behind the membrane block to polygamy. They studied sexual reproduction in
the unicellular green alga Chlamydomonas. The researchers found that two
proteins, FUS1 and HAP2, that are required for membrane fusion between plus
and minus mating-type gametes, are both degraded immediately after fusion,
preventing polygamy. Using fusion-defective strains, they also show that it is
membrane fusion that triggers degradation of the proteins, and not the
gamete activation nor the adhesion that precedes fusion. Since HAP2 family
members are also involved in fertilization in higher plants (as well as in the
malaria organism, Plasmodium), the researchers suggest that this rapid
degradation mechanism could be a general feature of the membrane block to
polygamy.
DEVELOPMENT
Development 137 (9)