Basic HTML Version
15
Annual Review
2010/11
A
round the start of the twentieth century, the
great Spanish anatomist Santiago Ramón
y Cajal used Camillo Golgi’s impregnation
technique to observe and record the intricate
nature of the nerve cells that make up the
mammalian brain. His exquisite hand-drawn
images have stood the test of time, yet even
today neuroscientists continue to marvel and
in turn be frustrated by the myriad of cell types
present in our nervous systems. These are
the very cells whose diversity underpins every
aspect of our perception and understanding of
our surroundings, and whose failure, however
slight, can often have significant detrimental
effects on a person’s cognitive abilities. In
terms of the latter, one need only think of the
debilitating effect of Parkinson’s disease to
begin to fathom how missing one discrete
component can impact on the complex mesh of
interactions necessary for normal brain function.
Our research has gone back to the embryonic
development point when the nervous system exists
in its most primordial state – a single layer
of cells termed the neuroepithelium. At
this stage, the exact future role of each
of these cells is not defined, but they are
programmed to proliferate the tens of
billions of nerve cells that make up our
adult brain. More significantly, during
this phase the cells have the capability
to acquire the mature characteristics
of almost any nerve cell in the human
body. This property has led a number
of researchers to investigate the
mechanisms by which diversity arises,
as the ability to direct these multipotent
cells towards a given cell type would have
immense therapeutic potential.
Within the broad spectrum of nerve cells
present in the human brain, we have
decided to focus on a small population in
the cerebral cortex – the locally projecting
cells termed interneurons described by
Ramón y Cajal as the ‘butterflies of the
soul’. Deficits in these cells have been
implicated in neurological conditions as diverse as
bipolar disorder, epilepsy, autism, and the focus of
our current research – schizophrenia. Our recent
findings have revealed that the fate of an interneuron
is specified extremely early on in the embryo in
response to a genetic code, which acts through a
cascade of checkpoints to ensure we have the full
complement of mature cells in the adult brain. At
a basic level, this complex genetic system can be
thought of as barcode – a series of binary decisions
that a cell must make that push it towards its
eventual role. Using an array of genetic techniques,
we have begun to crack the code and are now able
to pinpoint where and when in the neuroepithelium
the various types of interneuron are born.
Unfortunately, from that point onward the story is still
largely incomplete, and we have little knowledge of
how interneurons acquire their correct functionality
in the newborn brain. The advent of new optical
and imaging tools has the potential to enable us to
examine just that, and, using the bits of code we
already know, we can identify the same cells time
and time again in the live brain. This allows us to
target our research more effectively and enables us
to begin to ask important questions as to the role of
individual types of cell within the developing brain. If
we can start to resolve how single populations act,
we will have the cornerstone to probe the newborn
brain further and understand how a simple layer
of cells in the embryo matures into the amazingly
complex adult brain.
As alluded to earlier, the implications for this line
of investigation do not end there. Media hype on
the potential of stem cell therapies to treat a range
of neurodegenerative ailments could remain just
that. However, by harnessing and directing these
multipotent cells through the cell type specific
developmental barcode, we could enable targeted
therapeutic intervention to attenuate a whole range
of debilitating conditions. A hundred years on from
Ramón y Cajal we are at the cusp of resolving the
diversity of cell types in our brains. Looking twenty
years into the future we might not regard nerve
cell diversity as an obstacle but rather as a tool to
treat conditions as disparate as schizophrenia and
Parkinson’s disease.
Above:
A ‘butterfly of the soul’. Fluorescent labelling of individual populations
of nerve cell in the brain enables us to gain a better understanding of how they
contribute to normal and conversely dysfunctional brain activity.
Left:
Viewed
in a cross section of the embryonic brain, two genetic programs (labelled with
green and red fluorescent probes) can be observed as they begin to direct the
proliferation and fate of the billions of nerve cells that will eventually populate
our adult brains.
Images: Simon Butt