Researchers at the Johns Hopkins University School of
Medicine and Washington University
School of Medicine have identified a key to eye
development: a protein that regulates how the light-
sensing nerve cells in the retina form. While still far
from the clinic, the latest results, published in
the Jan. 29 issue of Neuron, could help scientists
better understand how nerve cells develop.
"We've found a protein that seems to serve as a
general switch for photoreceptor cell
Seth Blackshaw, an assistant professor in the Solomon
H. Snyder Department of
Neuroscience at Johns Hopkins. "This protein coordinates
the activity of multiple proteins, acting like
a conductor of an orchestra, instructing some factors to be
more active and silencing others, and thus
contributing to the development of light-sensitive cells of
Blackshaw's laboratory is trying to understand the
steps necessary for developing light-sensitive eye cells to
transition into one of two types, rod or cone. Any
breakdown in the development
of either type of cell can lead to impaired eyesight and,
Blackshaw said, "the loss of cone cells in
particular can lead to irreversible blindness." Rod cells
help us see in dim or dark light; cone cells help
us see bright light and color.
The research team was interested in how other genes
that are active in the developing retina
can act to promote the development of rod cells while
suppressing the development of cone cells. So
they took a closer look at the candidate protein Pias3,
which is short for protein inhibitor of activated
Stat3. Pias3 was known to alter gene control in cells
outside the eye. In these cells, Pias3 doesn't
directly turn genes on and off but instead adds a chemical
tag — through a process called
SUMOylation — to other proteins that do switch genes
on and off. And, since Pias3 also is found in
developing rod and cone and no other cells in the eye, the
team hypothesized that it might act to help
these cells "decide" which type to become.
To determine whether Pias3 orchestrates rod cell
development, the researchers used mice.
First, they engineered mice to make more Pias3 than normal
in the eye and counted rod and cone cells.
Those eyes contained more rod cells than eyes from mice
containing a normal amount of Pias3 protein.
When they reduced the amount of Pias3 in developing mouse
eyes, they found that the cells that
might otherwise have been rod cells instead developed into
conelike cells. So the team concluded that
Pias3 promotes rod cell development and suppresses cone
Next they wanted to know if Pias3 works the same in
eye cells as it does in other cells, through
SUMOylation. The team altered the Pias3 protein to disrupt
its SUMOylation activity. They found
that eyes containing altered Pias3 did not develop the
correct number of rod cells, suggesting that
Pias3's SUMOylation activity was the key to its ability to
promote rod and suppress cone cell
development in the eye. The team also found that Pias3
SUMOylates a protein, Nr2e3, already known
to influence rod and cone cell development, and showed that
SUMOylation is critical for its ability to
repress cone development.
Blackshaw said he hopes that his basic research
results will contribute to translational and
clinical research to generate more treatment options for
blinding conditions, such as macular
degeneration, that arise from rod and cone cell death.
"Future treatments might be designed to
pharmacologically manipulate Pias3-dependent SUMOylation
and potentially convert photoreceptors to
a cone fate, thus providing a treatment for forms of
inherited blindness that selectively result in the
death of cone photoreceptors," Blackshaw said.
This research was funded by the National Institutes of
Health, Alfred P. Sloan Foundation,
W.M. Keck Foundation, Japan Society for the Promotion of
Science and Research to Prevent Blindness.
Authors on the paper are A. Onishi, U. Alexis and
Blackshaw, all of Johns Hopkins; and G. Peng,
C. Hsu and S. Chen, all of Washington University.