Inside Salk - October 2009 - page 20

N EWS B R I E F S
I N S T I T U T E N EW
Salk scientists report that Fgf10, amemberof the fibroblast growth
factor (Ffg) family of morphogens, lets brain stem cells know when it’s time to get to
work, ensuring they hit their first developmental milestone at the right moment.
Their findings not only add new insights into brain development and a novel function
for Fgfs, but also reveal a possiblemechanism for the selective expansion of specific
brain areas over the course of evolution, such as the greatly increased size of the frontal
lobe in humans.
During embryonic brain development, stem cells in charge of building the cortex—
the largest brain structure and seat of most higher cognitive functions—pass through a
series of tightly regulated stages: from omnipotent stem cell to cortical progenitors cells
capable of producing neurons.
“The timing of each of these transitions has critical implications for brain devel-
opment, sinceminor changes in the proportion of progenitors exhibiting one or the
other divisionmode at early stages will result in substantial changes in the number of
neurons and the size of the cortex,” says
Dennis O’Leary
, a professor in theMolecular
Neurobiology Laboratory, who led the study.
Early in corticogenesis, stem cell-like progenitor cells known as neuroepithelial cells
undergo symmetric cell division, producing two identical progenitors to expand the pool
of neuroepithelial cells. Later on, they differentiate intomoremature progenitor cells
referred to as radial glia, which then divide asymmetrically to produce a pair of unlike
daughter cells: one radial glia tomaintain the pool of progenitor cells and a cortical
neuron or a basal progenitor. The latter will migrate outward and then produce neurons
to establish the superficial layers of the cortex.
But little is known about themechanisms that mediate the critical transition period
that bridges the early expansion phase of neuroepithelial cells and the later neurogenic
phase, which produces all the neurons that will eventually form the six layers of
the cortex.
“These findings demonstrate a direct mechanism employed during normal develop-
ment to regulate brain size,” says O'Leary. “These findings also have potential implica-
tions for how cortical areas have evolved. Selectively expanding the progenitor pool by
Fgf10 regulation of the timing
of radial glia differentiation
could account for the selective
expansion of the frontal cortex,
which has been greatly expanded
in humans and is thought to
be important for evolving what
are considered typically human
traits.”
Discovery Roundup
Growth Factor Keeps Brain Development on Track
Tumor suppressor
pulls double shift
as reprogramming
watchdog
Acollaborativestudybyresearchers
at the Salk Institute uncovered that the tumor
suppressor p53, whichmade its name as
“guardian of the genome,” not only stops cells
that could become cancerous in their tracks
but also controls somatic cell reprogramming.
Although scientists have learned how to
reprogram adult human cells such as skin cells
into so-called induced pluripotent stem cells
(iPSCs), the reprogramming efficiency is still
woefully low. The Salk study, published in the
Aug. 9 advance online edition of Nature, gives
new insight into why only a few cells out of
many can be persuaded to turn back the clock.
“Althoughwe have been able to reprogram
specialized cells for a while now, there had been
nothing known about the control mechanisms
that prevent it from happening spontaneously
in the body andwhy it has been so hard to
change their fate in a Petri dish,” says
Juan-Carlos Izpisúa Belmonte
, a professor in
the Gene Expression Laboratory, who worked
closely with
GeoffreyM. Wahl
, also a professor
in the Gene Expression Laboratory.
Their findings bring iPSCs technology a
step closer to fulfilling its promise as source
of patient-specific stem cells but also force
scientists to rethink the development of cancer.
“There’s been a decade-old idea that cancer
arises through the de-differentiation of fully
committed and specialized cells but eventually
it was discarded in favor of the currently
fashionable cancer stem cell theory,” says
Wahl. “Now that we know that p53 prevents
de-differentiation, I believe it is time to
reconsider the possibility that reprogramming
plays a role in the development of cancer
since virtually all cancer cells lose p53
function in one way or another.”
20
Inside SalkOctober 2009
Without Fgf10 (right), neuronal stem cells fail
to differentiate on time. As a result, they keep
multiplying and generate a bigger pool of radial
glia (shown in red).
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