IN THIS ISSUE
Nf2 regulates neural progenitor
proliferation
Mutation of neurofibromatosis 2 (NF2) results in nervous
system tumours. Molecularly, Nf2 has diverse functions,
regulating cell-cell junction formation and various
signalling pathways, including the Hippo-Yap pathway.
However, the roles of Nf2 in the nervous system, and how its loss promotes
tumorigenesis, are poorly understood. Here (p. 3323), Xinwei Cao and coworkers analyse the consequences of Nf2 deletion in the dorsal telencephalon.
Although the mutant mice are viable, they display significant brain
malformations associated with neural progenitor cell (NPC) hyperproliferation.
To determine how Nf2 limits NPC expansion, the authors performed a
microarray analysis and found many known targets of the transcriptional
coactivator Yap upregulated upon Nf2 deletion, suggesting that Nf2 may
inhibit Yap activity. Consistent with this, protein levels and nuclear localization
of Yap and its paralog Taz are increased in Nf2 mutants. Moreover, Yap deletion
rescues the Nf2 mutant phenotype – demonstrating the functional importance
of this regulation. These data uncover a key role for Nf2 and Yap/Taz in
regulating NPC proliferation in the developing brain.
Staying in sync through
development
During embryogenesis, transcriptional regulation
must be coordinated with growth and cell
division, so that genes are turned on or off in the right cells at the right time.
Arjun Raj and colleagues now investigate the coupling of gene expression and
cell division in C. elegans (p. 3385). They find that global retardation of
development by temperature change or gene mutation slows down the cell
cycle, and this is accompanied by a similar delay in expression of particular
developmental genes – so the synchrony between cell cycle and gene
expression is retained. These findings suggest that transcription might be
directly cell cycle dependent. However, mutations that cause cell cycle delays
in specific lineages uncouple cell division and transcription, arguing against the
onset of transcription being tied to a particular division cycle. Conversely, it is
known that cell division in C. elegans embryos proceeds independently of
zygotic transcription. Together, these data demonstrate that cell proliferation
and gene expression are well synchronised, but raise the key question of how
this synchrony is achieved.
How cilia know which way to point
Cells lining the lumen of various organs, such as the lung
airway and the female reproductive tract, are
multiciliated, and all the cilia are oriented in the same
direction to generate flow. But how is cilia orientation
coordinated within cells and across tissues? Chris Kintner and colleagues use
the epithelial cells of Xenopus embryos as a model to study multicilate cell
differentiation. On p. 3468, they identify a new regulator of cilia polarisation,
the coiled-coil protein bbof1. Bbof1 is expressed in multicilate cells and localises
to the axoneme and the basal body – the structure that determines cilia
orientation. Upon bbof1 depletion, motile cilia still form, but are unable to
generate significant flow because their orientation is disturbed. Notably, bbof1
is not required for the initial phase of cilia polarisation, but rather for the later
refinement step, and for stabilising the alignment. Although the mechanism
by which bbof1 acts remains unclear, this work identifies a key factor
regulating cilia orientation and function.
Go with the flow: circulating BMP
promotes endothelial quiescence
Blood flow through the developing vasculature
regulates vessel formation – both via the distribution
of endocrine factors, and via mechanical forceinduced responses. Several signalling pathways are known to be involved
in this process, including signalling via the TGFb receptor Alk1, whose
activity promotes quiescence in newly formed arteries and whose
expression is itself dependent upon blood flow. On p. 3403, Beth Roman
and colleagues demonstrate that not only Alk1 expression but also its
activity are dependent upon blood flow in developing zebrafish. They
identify Bmp10 as the endogenous ligand for Alk1 in this context, and find
that Bmp10 is exclusively expressed in the heart, and not in the vascular
tissue. Through elegant experiments using embryos in which the heart has
been stopped but alk1 expression restored, they show that Bmp10
injection can locally rescue Alk1 pathway activity and downstream
transcriptional responses. Thus, their data suggest that blood flow is
required to distribute cardiac-derived Bmp10 into the vasculature, where
it activates Alk1 to promote quiescence in endothelial cells.
Histone methylation: not so dynamic
after all
Polycomb group proteins are chromatin regulators with
highly conserved functions. The Polycomb repressive
complex 2 (PRC2) methylates H3K27 to stably silence
target genes, including the HOX genes in Drosophila.
More recently, Utx and Jmjd3 demethylases were found to reverse PRC2mediated H3K27 methylation, and it has been suggested that a dynamic cycle
of methylation and demethylation is required for appropriate regulation of
gene expression. Now, Ömer Copur and Jürg Müller challenge this view
(p. 3478), via the analysis of Drosophila Utx mutants. Lack of zygotic Utx
function has no effect on Drosophila development, although mutant adults die
shortly after hatching. Loss of both maternal and zygotic Utx, however, leads
to larval death and to defects in HOX gene expression – in both the embryo
and larval imaginal discs. Thus, it appears that Utx in Drosophila – and, by
inference, H3K27 demethylation – is required only at early stages to set up the
patterns of HOX expression; it is largely dispensable later in development,
suggesting that H3K27 methylation may in fact be very stable.
An integral role for integrin b1 in the
pancreas
Integrins mediate cell-matrix adhesion and are also
capable of inducing intracellular signalling cascades to
regulate cell proliferation, differentiation and other cell
behaviours. In vitro, disruption of b1 integrin function has been shown to affect
various aspects of pancreatic b-cell activity. On p. 3360, Vincenzo Cirulli and coworkers analyse the consequences of deleting b1 integrin in b-cells in vivo in
mice. The mutant mice have smaller pancreatic islets that exhibit matrix adhesion
defects when cultured in vitro. Notably, cell proliferation is severely impaired in
the mutant b-cells, and the expression of cell cycle regulators is highly abnormal.
However, these cells are able to differentiate properly and to express insulin, and
are glucose responsive; in fact, they show increased levels of insulin and the
mutant mice show no signs of diabetes. These results highlight differences
between the ascribed functions of b1-integrin in vitro versus in vivo and define
its key role in promoting proliferation during pancreatic islet development.
DEVELOPMENT
Development 140 (16)