To build or repair a car, you
generally need to know a fair bit
more than just how it works. Yet
today we seek to repair brains
ravaged by disease in the absence of
any real knowledge about how they
work, and only a sparse knowledge
of how they are built.
Transplantation of stem cells or
tissues alone is not sufficient to
restore function in diseases or
injury. New neural components —
wetware or hardware — must be
integrated in a way that augments
existing function, and permits them
to successfully compete for resource
and control.
What we do know is that the
population of the developing cortex
by its cellular inhabitants is a mass-
migratory event that proceeds with
the utmost of precision.
A recent
publication in Cell uncovered a few
of the molecular players in this
game. The paper sought to reveal
how developments ultimately shape
the unique structure of the cortex
through the manipulation of tractile
and tensile forces. In probing these
components, researchers stumbled
upon one that makes a mouse brain
turn out decidedly more human in
appearance.
Highly convoluted and richly
textured, the exterior surface of the
human brain is instantly
recognizable. Nothing says “what a
marvelous structure” like a deeply-
fissured glob of goo. There are
individual differences, but the basic
plan reliably emerges in
development, day in and day out.
With the advent of MRI scanning, we
have discovered that, occasionally,
people are born with a smooth
cortex as a result of certain genetic
mutations. For them, severe
neurological impairment and early
death are inevitable.
Back in 2003, it was discovered that
the normally smooth cortex of the
mouse could be made to develop
rudimentary folds reminiscent of the
brains of larger mammals. These
brains did not actually have the
deep grooves (known as sulci and
gyri) which would be representative
of the true folds of a mammalian
cortex. The gene that was
manipulated to do this is one that
regulates cell proliferation. By
engineering changes in this gene in
mice, the researchers were able to
create a thinner cortex of greater
surface area, which necessarily
kinked throughout its upper surface
within its bony confines.
The new research reported in Cell,
builds on the earlier thesis work of
Ron Stahl, who previously
demonstrated that the protein
product of a gene known as TRNP1
programs cells either for continued
multiplication, or to turn into a
mature cell which is done dividing.
Working together with Magdalena
Götz in Munich, they now show how
TRNP1 is involved in the
specification of radial and tangential
expansion of discrete regions of
growing cortex.
They also show that one of the main
regulatory points is controlling the
number of scaffold cells called radial
glial cells. These cells are the among
the first to populate the cortex,
creating, in effect, a rough blueprint
for the brain. These cells normally
set up an elaborate trusswork upon
which neural cells migrate, much
like the support lattices frequently
installed for growing tomato plants.
To demonstrate these effects, the
researchers used a process called
“electroporation” to introduce
specially-designed RNA into localized
areas of the developing mouse
cortex. Electroporation creates
transient pores into cell membranes
which allow small molecules to
enter. Once inside, the RNA probe
interferes with the production of the
TRNP1 protein. The end result of
this is an increase in the number of
radial glial cells. That leads to more
neuronal migration, and a thicker
cortex which necessarily bulges to
form gyri.
Intriguingly, another effect of the
TRNP1 manipulation was a clear
shift in the number of precursor
cells observed to divide with their
cleavage axis oriented horizontally
to the plane of the cortex. Control
of cleavage axis is a well established
mechanism for cortical specification
which gives the daughter cells a
head start not only in migration
direction, but in selective adherence
to the guiding scaffold.
The researchers also obtained
human tissue samples from
preserved brains dating to weeks
12, 18, and 21, the period of time
during pregnancy when the cells of
the cortex are rapidly dividing.
Consistent with the mouse
experiments, they found that TRNP1
was present at levels that correlated
locally with presence of folds. It is
worth reiterating that there are vast
differences in scale between human
and mouse brains.
Some features of the cortex, like
thickness, are roughly similar at
around 3mm, while others such as
surface area, differ a thousand-fold.
Indeed a single gyrus in a human
brain is comparable in size to the
entire cortex of a mouse. It is
therefore quite remarkable that
similar molecular mechanisms are at
play in the development of both.
New functionality has apparently
been introduced to older pathways
that, at least in smooth brains,
formerly had nothing to do with
folding.
Much of the phenomena involved in
folding are physical. Axons, for
example, tug more tightly on
regions of the cortex that are the
first to mature. The forces that lead
to buckling of the cortex are set up
by differentially-controlled
proliferation and migration of cells
which ultimately take orders from
molecular cues.
Development in brains eventually
reaches a steady state as many of its
programs wind down. Yet, when
viewed under a microscope, the
brain can still be observed to be in a
state of constant flux which
recapitulates many of these
developmental processes. As
researchers continue to lay bear the
elements that shape this growth,
integration of new cells and tissues
to augment the brain will proceed
much more smoothly.
Developments like this one may
seem out there, and unrelated to
the some of the more practical goals
we have for brain research today,
but each marks a notable step in
understanding how the mammalian
brain develops and, ultimately,
functions. More specifically, because
we are doing so many studies that
involve putting human cells into
mice for testing, it's important that
we know how the mouse brain
normally develops.
In addition to
shedding light on some new
mechanisms of brain development,
this research also demonstrates how
old genes are involved in building
new structure in more evolved
mammalian brains.
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