Insight into a
specific gene pathway that appears to regulate the growth, structure,
and organization of the human cortex has been illustrated by a research published in the journal Cell Stem Cell.
They also demonstrate that 3D
human cerebral organoids - miniature, lab-grown versions of specific
brain structures - can be effective in modeling the molecular, cellular,
and anatomical processes of human brain development. And they suggest a
new path for identifying the cells affected by Zika virus.
‘Increased proliferation of neural progenitor cells (NPs) induces expansion of cortical tissue and cortical folding in human cerebral organoids.’
One of the most significant ways in which the human brain is unique
is the size and structure of the cerebral cortex. But what drives the
growth of the human cortex, likely the foundation for our unique
"We found that increased proliferation of neural progenitor cells
(NPs) induces expansion of cortical tissue and cortical folding in human
cerebral organoids," says Yun Li, a lead author of study and
post-doctoral researcher at Whitehead Institute. "Further, we determined
that deleting the PTEN gene allows increased growth factor signaling in
the cell, unleashing its growth potential, and stimulating
These findings lend support to the notion that an increase in the
proliferative potential of NPs contributes to the expansion of the human
cerebral neocortex, and the emergence of surface folding.
With normal NPs, the human organoid developed into relatively small
cell clusters with smooth surface appearance, displaying some features
of very early development of a human cortex. However, deleting PTEN
allowed the progenitor population to continue expanding and delayed
their differentiation into specific kinds of neurons - both key features
of the developing human cortex.
"Because the PTEN mutant NPs experienced
more rounds of division and retained their progenitor state for an
extended period, the organoids grew significantly larger and had
substantially folded cortical tissue," explains Julien Muffat, also a
lead author and post-doctoral researcher at Whitehead Institute.
In contrast, they found that while PTEN deletion in mouse cells does
create a somewhat larger than normal organoid, it does not lead to
significant NP expansion or to folding.
"Previous studies have suggested
that abnormal variation in PTEN expression may play an important role
in driving brain development conditions leading to syndromes such as
Autism Spectrum Disorders," says Rudolf Jaenisch, Founding Member of
Whitehead Institute and senior author of the study. "Our findings
suggest that the PTEN pathway is also an important mechanism for
controlling brain-structure differences observed between species."
The Whitehead investigators chose to focus on the PTEN gene because
it had previously been shown to have some function in cortical
development and to have a role in regulating progenitor cells of various
lineages. Notably PTEN loss-of-function mutations have been associated
with human microcephaly.
In this study, deletion of the PTEN gene increased activation of the
PI3K-AKT pathway and thereby enhanced AKT activity in the human NPs
comprising the 3D human cerebral organoids; it promoted cell cycle
re-entry and transiently delayed neuronal differentiation, resulting in a
marked expansion of the radial glia and intermediate progenitor
Validating the molecular mechanism at work with PTEN, the
investigators used pharmacological AKT inhibitors to reverse the effect
of the PTEN deletion. They also found that they could regulate the
degree of expansion and folding by tuning the strength of AKT
signaling - with reduced signaling resulting in smaller and smooth
organoids, and increased signaling producing larger and more folded
Finally, the researchers utilized the 3D human cerebral organoid
system to show that infection with Zika virus impairs cortical growth
and folding. In the organoids, Zika infection at the onset of surface
folding (day 19 of development) led to widespread apoptosis; and, ten
days later, it had severely hampered organoid growth and surface
folding. Zika infection of four-week-old organoids, showed that PTEN mutant
organoids were much more susceptible to infection than normal control
organoids; notably, they showed increased apoptosis and decreased
proliferation of progenitor cells.
"Although not an original goal of our study, we have demonstrated
that 3D human cortical organoids can be very effective for Zika
modeling - better enabling researchers to observe how human brain tissue
reacts to the infection and to test potential treatments," Li says.