Download PDF

IN THIS ISSUE
Cofilin and Vangl2 kick start
planar cell polarity
The planar cell polarity (PCP) pathway orients cells
within the plane of an epithelium during
development. Experiments in Drosophila indicate
that the core PCP proteins move to the apical cell membrane during the
initiation of PCP and implicate the actin-severing protein cofilin in PCP
initiation. Now, on p. 1262, Kathyrn Anderson and colleagues report that
cofilin 1 (Cfl1) and the core PCP protein Vangl2 cooperate to control PCP
initiation in the mouse embryo. The researchers analyse two aspects of PCP –
convergent extension of the axial midline and posterior positioning of nodal
cilia. Both these aspects of PCP are nearly normal in Cfl1 and Vangl2 single
mutants, they report, but midline extension fails completely and nodal cilia do
not polarise in Vangl2 Cfl1 double mutants because PCP protein complexes fail
to move to the apical cell membrane. These and other results suggest that
remodelling of the actin cytoskeleton is required to traffic vesicles containing
PCP proteins to the apical membrane during PCP initiation.
Chromatin remodelling in vein
specification
Arteries and veins are structurally and functionally distinct
vessels that circulate blood away from and towards the heart,
respectively. Notch signalling determines arterial specification
during development whereas the orphan nuclear receptor COUP-TFII (also known
as NR2F2) promotes venous specification by inhibiting Notch signalling in a subset
of endothelial cells. But what regulates COUP-TFII expression in veins? Courtney
Griffin and co-workers now report (p. 1272) that the chromatin remodelling
enzyme BRG1 promotes COUP-TFII expression and venous specification during
mouse embryogenesis. The researchers show that genetic depletion of Brg1
downregulates COUP-TFII expression and leads to aberrant expression of arterial
markers in developing veins. BRG1 promotes the expression of COUP-TFII, they
report, by binding to regulatory elements within the COUP-TFII promoter and
remodelling the chromatin to increase the promoter’s accessibility to the
transcriptional machinery. These data describe for the first time a factor that
promotes COUP-TFII expression in developing veins and broaden our
understanding of how epigenetic processes influence vascular development.
Airn silencing: self-sufficient but
reinforced
Epigenetic processes control the parental-specific
(imprinted) expression of a subset of mammalian genes.
For example, the paternally expressed imprinted long noncoding (lnc) RNA Airn initiates paternal-specific silencing of Igf2r, a gene that
is essential for development. Airn initiation of Igf2r silencing is followed by gain
of DNA methylation on the silent Igf2r promoter. Here (p. 1184), Denise
Barlow, Florian Pauler and colleagues investigate the control of Igf2r silencing
during mouse embryonic stem cell (ESC) differentiation. By turning Airn
expression off during ESC differentiation, the researchers show that continuous
Airn expression is needed to maintain Igf2r silencing until the paternal Igf2r
promoter is methylated. By conditionally turning Airn expression on, they show
that Airn can initiate Igf2r silencing throughout ESC differentiation and that
silencing is maintained in the absence of DNA methylation. Thus, Airn lncRNA
is necessary and sufficient to silence Igf2r throughout ESC development
whereas DNA methylation is dispensable for silencing initiation and
maintenance but reinforces Igf2r silencing.
T cell to myeloid cell switch
T cells develop from multipotent progenitors
in the thymus. Initially, these progenitors can
generate myeloid cells, B lymphocytes and T
cells but, as differentiation proceeds, they become committed to the T-cell
lineage. On p. 1207, Marissa Morales Del Real and Ellen Rothenberg
investigate the regulatory network that controls this process. Previous studies
have shown that the decision to become a T cell can be opposed by the
myeloid cell transcription factor PU.1 but that exposure to Notch signalling
determines the developmental outcome of expressing PU.1. The researchers
now show that Notch signalling does not inactivate the PU.1 protein but
instead re-channels its transcriptional effects to maintain a T-cell transcriptional
network. They describe two branches of this network – one that involves basic
helix-loop-helix E proteins in a positive-feedback loop with Notch, and one in
which PU.1 can inhibit T-cell transcription factor genes such as Gata3 only if
Notch signalling is absent. Together, these results provide new insights into the
complex architecture of a lymphomyeloid developmental switch.
Hear, hear! Postnatal cochlear cell
progenitors
Irreversible damage of cochlear sensory hair cells and
nonsensory supporting cells causes permanent hearing loss
because the sensory epithelium cannot repair or regenerate
itself postnatally. Active Wnt/-catenin signalling marks many endogenous
stem cells and Roel Nusse, Alan Gi-Lun Cheng and colleagues now report
(p.1196) that tympanic border cells (TBCs), which lie beneath the sensory
epithelium, are Wnt responsive and can act as progenitors for sensory epithelial
cells in the postnatal mouse cochlea. The researchers show that transient but
robust Wnt signalling and proliferation exists in TBCs during the first 3
postnatal weeks and report that Wnt agonists stimulate the proliferation of
TBCs in cochlear explants. Moreover, TBCs that express the Wnt target gene
Axin2 can generate new hair cells and supporting cells in vivo and in vitro. The
researchers suggest, therefore, that TBCs serve as a reservoir of cells for the
intricate organisation of the cochlea during early postnatal development and
that quiescent TBCs in the adult cochlea might represent targets for
regenerative therapy.
Tumour suppression trafficked
by Atg6
Autophagy is a conserved catabolic process that
degrades the cell’s own components through the
lysosomal machinery in response to cell stress.
Atg6/beclin 1 is a core component of the mammalian vacuolar protein sorting
34 (Vps34) complex that is required for autophagy. It is also a tumour
suppressor, a function that has been attributed to its role in autophagy. But
could the potential function of Atg6/beclin 1 in other vesicle trafficking
pathways be involved in tumour development? On p. 1321, Eric Baehrecke
and co-workers generate Atg6 mutant Drosophila and show that Atg6 is
essential for autophagy, endocytosis and protein secretion. By contrast, the
core autophagy gene Atg1 is required for autophagy and protein secretion
only. Consistent with the tumour suppressor role of beclin 1, loss of Atg6
causes over-production of blood cells and the formation of melanotic blood
cell masses. Together, these results suggest that the involvement of Atg6/beclin
1 in multiple vesicle trafficking pathways
underlies its role as a tumour suppressor.
Jane Bradbury
DEVELOPMENT
Development 140 (6)