Neural stem cell study reveals mechanism that may play role in cancer
In the dynamic world of the developing brain, neural stem cells give
rise to neurons deep within the brain's fluid-filled ventricles.
These newborn neurons then migrate along the stem cell fibers up to
the neocortex, the seat of higher cognitive functions. Now,
scientists have discovered a key mechanism of this migration – one
that may also play an important role in other developmental processes
and diseases, including cancer.
The finding, the cover story in a recent issue of Nature (Aug. 23,
2007), was led by Laura Elias, a neuroscience graduate student in the
laboratory of senior author Arnold Kriegstein, MD, PhD, a professor
of neurology and director of the UCSF Institute for Regeneration
Medicine.
Elias is one of 16 UCSF CIRM Stem Cell Scholars – up and coming young
scientists funded by the California Institute for Regenerative
Medicine, established by California voters in 2004 to allocate $3
billion over 10 years to support stem cell research.
Scientists have known that migration of neurons depends in part on
motors within the cells that drive their movement along the neural
stem cell fibers. They have also known that this migration depends on
receptors on the neurons' surface that sense signals in the
environment that either repel or attract the cells, thus directing
their path.
But little has been known about the molecules that mediate the
interaction between the migrating neurons and the neural stem cell
fiber itself. And relatively overlooked in this process has been the
possible role of so-called "gap junctions."
Gap junctions are pores, or channels, that form between cells. They
are created when two hemi-channels, each in the membrane of a
different cell, connect. The junctions are well known for their role
in enabling cells to pass molecular signals to one another. In
developing tissue, they are particularly active in supporting
signaling that promotes cell proliferation, or cell division.
In the current study, however, the team made the unexpected finding
that gap junctions also play a crucial role in neuronal migration –
and that they function in a previously unrecognized way. Rather than
functioning as a conduit through which molecular signals move, the
two fused hemi-channels serve as a form of adhesion between the
migrating neurons and the neural stem cell fibers.
Cell adhesion is a common mechanism, but its function had not been
detected previously in gap junctions.
The discovery that gap junctions were involved in migration in any
capacity was a surprise. Elias had been investigating whether the
molecule functioned as a channel to regulate cell proliferation
within embryonic neural stem cells of the developing rat brain,
building on preliminary findings from the Kriegstein lab 15 years
ago.
As part of one study, she had reduced the levels of gap junctions in
the neural stem cells. "To our surprise," she says, "the newborn
neurons that the stem cells produced piled up on one another and
failed to migrate into the cortex."
To establish the role that gap junctions might play in neuronal
migration, the team focused on the activity of the molecule's
subunits, known as connexons, in a series of studies in the
developing rat brain. They honed in on two of these proteins – Cx26
and Cx43 – because they determined that they were expressed at high
levels in migrating neurons and along radial fibers and that they
were, in fact, highly localized in regions of the neurons that were
in contact with radial fibers.
In a notable finding, says Elias, blocking the activity of either
subunit significantly impaired migration to the neocortex, as seen in
a "striking cellular redistribution pattern of the neurons."
To determine the mechanism by which the gap junctions were
functioning, the team selectively blocked three plausible mechanisms:
the well-known channel function, a form of cellular signaling that
relies on the intracellular end of the molecule, and adhesion.
"Remarkably,
neuroscience program at UCSF and a member of the Kriegstein lab, "we
found that adhesion, alone, is necessary for the role of gap
junctions during neuronal migration."
Further study revealed that the Cx43 and Cx26 molecular subunits
interact with the neuron's internal cytoskeleton to stabilize it on
its path.
A series of time-lapse, live imaging studies of migrating neurons
illuminated this phenomenon: The neurons start out with a branched
leading process. Then one of the processes is stabilized and the
neuron translocates its body into a swelling that forms in the
stabilized leading process. When the levels of the gap junction
protein are reduced, however, the neurons are no longer able to
stabilize their leading processes and continue to send out multiple
branches.
The revelation of the gap junction's role in neural migration is
provocative, says Kriegstein, because the molecule is known to be
involved in several disease processes, including the spread of
cancers in the brain, skin and lung. Most brain tumors are made up of
glial cells that spread throughout the brain by migrating along white
matter pathways -- the network of neural fibers that connect neurons.
While roles for the gap junction channel in cancer have been
demonstrated, "It's possible," he says, "that gap junctions are also
using the cell adhesion function in these disease settings to support
cell migration. If so, the mechanism could become a target for
therapy."
The study also revealed another surprising phenomenon, says
Kriegstein, the John G. Bowes Endowed Chair in Stem Cell and Tissue
Biology. It has long been known that when neural stem cells divide
they undergo a process of asymmetrical division, in which they
produce one newborn neuron and one new neural stem cell. The
understanding has been that the neurons then begin their migration
along the radial fibers to the neocortex.
But the study revealed that newborn neurons and the newborn neural
stem cell stick together for a significant period of time, up to many
days, while the newborn neuron migrates to the cortex, and they are
stuck together by the gap junctions. It's possible, says Kriegstein,
that the adhesion function is allowing the gap junction to also
support signaling through the gap junction channel between the neural
stem cell and its daughter neuron.
The discovery of the gap junction's adhesion capacity also offers a
window into its evolutionary history, says Kriegstein. "The molecule
may have been functioning for some time as an adhesion molecule," he
says. "It couldn't very well form a channel between two neighboring
cells unless the two halves of the channel first stuck together."
The team's understanding of neuronal migration in the developing
brain also appears likely to evolve. The discoveries they've made in
this study, like the processes of the migrating neuron, are moving
them forward with new hypotheses to investigate.
The study was funded by the National Institutes of Health, the
Sandler Family, Genentech Graduate Fellowship, the California
Institute for Regeneration Medicine, and the J.G. Bowes Research Fund.
UCSF is a leading university that advances health worldwide by
conducting advanced biomedical research, educating graduate students
in the life sciences and health professions, and providing complex
patient care.
###
Related links:
For visuals of neuronal migration:
http://www.yousendi
action=batch_
UCSF Institute for Regeneration Medicine
http://irm.ucsf.
Kriegstein lab
http://www.irm.
Source: Jennifer O'Brien
jobrien@pubaff.
415-476-2557
04 September 2007
http://pub.ucsf.
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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