Heidelberg University (Germany) researchers transform classical understanding through in vivo analysis of eye development.
In an in vivo analysis of eye development, researchers at
Heidelberg University and the University of Freiburg have gained
fundamental new insight into the development of coloboma of the eye,
prompting them to revise the classical view of the development of this
sensory organ in vertebrates. The team led by developmental and cell
biologists Dr. Stephan Heermann and Prof. Dr. Jochen Wittbrodt of the
Heidelberg Centre for Organismal Studies (COS) used in vivo 4D
microscopy to demonstrate that directed tissue flow transforms the optic
vesicle into the optic cup during eye development. This is not only
critical for understanding the cause of coloboma (“cat eye syndrome”),
but also means that eye development in vertebrates, including humans, is
fundamentally different than has been taught for more than 70 years.
The results of their research were published the journal eLife.
In their analysis, the research group, which included Prof. Dr.
Kerstin Krieglstein of the Department of Molecular Embryology at the
Institute of Anatomy and Cell Biology of the University of Freiburg,
combined modern genetics with time-lapse microscopy of living cells.
This allowed them to record the dynamics of organ morphogenesis. They
made three fundamental discoveries in the process. “We now know that
that an organ forms through flow, not incrementally in steps. If the
flow is stopped, coloboma develops. And we found the source of the stem
cells in the eye, which is of major importance in stem cell research,”
explains Prof. Wittbrodt.
The eye is an outgrowth of the brain and forms in the embryo from a
sac-like vesicle that quickly transforms into an optic cup with an
interior retina surrounded on the outside by pigment epithelium. Major
problems result if this step fails; the optic cup does not close and
results in a coloboma, one of the most frequent causes of paediatric
blindness.
Until now, the optic cup was believed to develop rather statically
from two layers of the vesicle, with the lens-facing layer becoming the
retina and the other, lens-averted layer forming the pigmented
epithelium. “However in the detailed investigation of this developmental
step using high-resolution video microscopy on living fish, we
discovered that the optic cup forms from a dynamic flow of lens-averted
cells into the lens-facing optic cup, exactly the opposite of static
development,” explains Dr. Heermann. The researchers also found the
growth factor that controlled the flow of tissue and was thus essential
for eye development. The signalling pathway of the growth factor BMP
must be modulated for the tissue to flow and transform the vesicle into
the cup. “Without this modulation, the tissue remains stuck on the
lens-averted side and begins to develop into the retina,” continues
Stephan Heermann.
Yet another important finding of the study is the close connection of
movement (morphogenesis) and differentiation. It was already known that
precursor cells begin to differentiate into nerve cells of the retina
in the centre of the interior optic cup and continuously advance into
the periphery. “The new data gives us a completely new perspective on
this event,” explains Jochen Wittbrodt. The cells that differentiate
first are already located in the interior of optic cup at the start of
development. The cells that differentiate later do not flow into the
optic cup until later, and only there they are initially subject to the
influence of differentiation signals. Due to their position, these cells
are not exposed to the signals in the early phase. This is especially
true in the stem cells of the fish model system studied.
“Using 4D microscopy, we were now able to identify and analyse this
special population of cells,” explains Jochen Wittbrodt. It was clear
that there are two distinct areas in the lens-averted domain of the
developing optic cup, which is where these future stem cells are
initially located. These cells are the last to reach the optic cup and
end up at the boundary between the retina and the pigment epithelium.
“Our findings describe the origin of the stem cells in the eyes of fish
for the first time and imply that these cells are defined early. At
first glance this may not seem very interesting for humans, who no
longer have stem cells in the eye. But this data is extremely important
for stem cell research.”
According to Stephan Heermann, the current results have high
biomedical significance because they explain the origin of a coloboma.
The bifurcated flow of tissue described creates a fissure on the
underside of the eye, the optic fissure. As the eye continues to
develop, it is critical that this fissure close so the eye can see in
all directions. “The current data clearly indicates that both the
development of the optic fissure and its closure essentially depend on
the coordinated flow of tissue.” A coloboma is the medical term for an
open optic fissure.
Original publication:
S. Heermann, L. Schütz, S. Lemke, K. Krieglstein, J. Wittbrodt: Eye
morphogenesis driven by epithelial flow into the optic cup facilitated
by modulation of bone morphogenetic protein. eLIFE, February 24, 2015,
doi: 10.7554/eLife.05216