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Development 137 (14)
Brainy signals for actin dynamics
During brain development, neurite outgrowth and
neuronal migration establish the brain architecture
needed for brain function. Now, Eric Olson and colleagues
reveal a regulatory feedback loop that links the
cytoskeletal changes that provide the mechanical force needed for neurite
outgrowth and migration to nuclear gene transcription during mouse brain
development (see p. 2365). Myocardin-related transcription factors (MRTFs),
the expression of which is forebrain enriched, translocate to the nucleus in
response to actin polymerisation and cooperate with serum response factor
(Srf) to regulate the expression of cytoskeletal genes. The researchers show that
either Mrtfa or Mrtfb is sufficient to support brain development but that the
brain-specific deletion of both produces brain abnormalities similar to those
caused by Srf deletion. These abnormalities, they report, are accompanied by
dysregulation of the actin-severing protein gelsolin and of the kinase Pctaire1,
which cooperates with Cdk5 to initiate a kinase cascade that governs
cytoskeletal rearrangements. The researchers suggest, therefore, that MRTFs
couple two signalling pathways that modulate cytoskeletal dynamics during
neurite outgrowth and neuronal development.
Proliferation’s not over ’til the
Fat-Hippo sings
During development, transitions from proliferating,
undifferentiated cells to quiescent, differentiated cells are
tightly regulated to ensure that organs reach the correct
size. Kenneth Irvine and colleagues now reveal that Fat-Hippo and Notch
signalling influence this important transition during optic lobe development in
Drosophila (see p. 2397). Like the vertebrate nervous system, the Drosophila
optic lobe develops from neuroepithelial cells, which function as symmetrically
dividing neural progenitors. The Fat-Hippo signalling pathway, which contains
the large cadherin Fat and the serine/threonine kinase Hippo, regulates the
transcription of cell proliferation and survival genes. The researchers report that
neuroepithelial cells in the Drosophila optic lobe undergo a cell-cycle arrest
that is regulated by Fat-Hippo signalling before converting to neuroblasts. They
also identify a role for Notch signalling in committing neuroepithelial cells to
become neuroblasts. These and other results suggest that, by arresting the cell
cycle, Fat-Hippo signalling contributes to the accumulation of Delta, which
modulates Notch signalling and triggers neuroepithelial differentiation. A
similar mechanism might be involved in vertebrate neural development.
IN THIS ISSUE
Integrin complexity at the heart of
angiogenesis
Integrin cell adhesion receptors and their ligand
fibronectin play important roles during diseaseassociated and developmental angiogenesis. However,
there are many different integrins, each of which contains a specific 
subunit and a specific  subunit, and it is not clear which  subunits are
involved in angiogenesis. Now, Arjan van der Flier and colleagues implicate
both 5 and v integrins, the major endothelial fibronectin receptors, in
vascular remodelling during mouse development (see p. 2439). The
researchers first show that, unexpectedly, the endothelial-specific knockout
of 5 integrin has no obvious effect on developmental angiogenesis. They
then test whether v integrins compensate for the absence of 5 integrins
by generating endothelium-specific 5; v double-knockout mice.
Vasculogenesis and angiogenesis are initially normal in these mice, but
subsequent remodelling defects in the great vessels and the heart
eventually cause embryonic death. Further investigations into the complex
interplay among integrins during angiogenesis revealed here could lead to
the development of effective anti-angiogenic drugs for cancer therapy.
Pancreatic plasticity: a mixed
message
The pancreas is a dual function organ. Acinar cells
in the exocrine gland make digestive enzymes,
which enter the intestine through ducts, while the islets of Langerhans in
the endocrine gland make insulin and other hormones, which enter the
blood system directly. However, insulin-producing (insulin+) cells also appear
in the hyperplastic ducts that develop in chronic pancreatitis and in
pancreatic cancer, which begs the question: do hyperplastic ductal cells and
their associated insulin+ cells have a common origin? On p. 2289, Anna
Means and colleagues use genetic lineage tracing and a mouse model that
develops insulin+-cell-containing hyperplastic ducts in response to growth
factor signalling to answer this question. They report that the hyperplastic
ductal cells arise largely from the transdifferentiation of acinar cells.
However, the insulin+ cells adjacent to the hyperplastic ducts arise from preexisting insulin+ cells that intercalate into the ducts as they develop, rather
than from insulin+ cell neogenesis, a result that has implications for efforts
to treat diabetes through  cell regeneration.
Pluripotent mouse embryonic stem (ES) cells are
obtained directly from the mouse epiblast, while
pluripotent embryonic germ (EG) cells can be derived from unipotent mouse
primordial germ cells (PGCs) by epigenetic reprogramming. But how similar are
EG and ES cells? On p. 2279, Azim Surani, Austin Smith and colleagues report
that these cells share a conserved molecular and developmental ‘ground state’.
ES cells can be established using the cytokine LIF combined with the inhibition
of GSK3 and of mitogen-activated protein kinase signalling (so-called 2i-LIF
culture). The researchers show that pluripotent mouse EG cells can also be
efficiently established using 2i-LIF culture. Then, using the same conditions,
they derive rat EG cells for the first time. These cells express similar markers to
rat and mouse ES cells, they report, and can contribute extensively to chimeric
rats. Together, these findings raise the possibility that 2i-LIF culture could be
used to derive EG cell lines with pluripotent ground state properties from other
species, including humans.
During vertebrate neural tube (NT) closure, the neural
plate bends and fuses to form the hollow structure from
which the CNS develops. Although neuroepithelial cell
elongation and apical constriction underlie this
morphological process, the role played by cytoskeletal elements in these cell
shape changes is poorly understood. On p. 2329, however, Naoto Ueno and coworkers report that the Xenopus orthologues of human MID1 (which encodes
the TRIM protein midline 1 and which is responsible for Opitz G/BBB syndrome)
and MID2 (a MID1 paralogue) regulate microtubule stabilisation during Xenopus
NT closure. The researchers show that knockdown of Xenopus MIDs (xMIDs)
disrupts epithelial morphology in the neural plate and leads to NT defects. This
abnormal phenotype, they report, is caused by microtubule destabilisation and
disorganisation in neuroepithelial cells. Furthermore, xMID knockdown disrupts
the morphogenesis of other epithelial organs. Thus, microtubule regulation by
the MIDs seems to be crucial for several epithelial remodelling processes, which
might explain the developmental abnormalities
seen in Opitz G/BBB syndrome.
Jane Bradbury
DEVELOPMENT
MID-way to neural tube closure
Pluripotent stem cell derivation
gets a (2i-)LIFt