University at Buffalo
BUFFALO, N.Y. – Scientists are developing a clearer
picture of how visual systems develop in mammals. The findings
offer important clues to the origin of retinal disorders later in
life.
In research
published this week in the Journal of Neuroscience, University at
Buffalo scientists and colleagues focused on a particular protein,
called a transcription factor, that regulates gene activity
necessary for the development of one type of retinal neuron, the
horizontal cells.
Horizontal cells process visual information by integrating and
regulating input from rod and cone photoreceptors, which allow eyes
to adjust to see well in both bright and dim light conditions.
“We have found that activation of the transcription factor
named Onecut1 is essential for the formation of horizontal
cells,” explains Xiuqian Mu, PhD, assistant professor in the
departments of Ophthalmology and Biochemistry in the UB School of
Medicine and Biomedical Sciences.
The researchers came to this conclusion after creating mice that
lacked Onecut1. In these knockout mice, the number of horizontal
cells was 80 percent lower than in normal mice.
The researchers were surprised to find that the removal of
Onecut1 also had an impact on photoreceptor cells, the rods and
cones that absorb light in the retina and convert that energy to an
electrical impulse eventually conveyed to the brain.
During development, Mu explains, the removal of Onecut1 only
appeared to impact the horizontal cells. However, by the time these
mice reached adulthood, around 8 months old, the level of
photoreceptor cells in these knockout mice was less than half the
normal level.
“Because degradation of photoreceptors is believed to be a
major factor in retinal diseases, such as retinitis pigmentosa and
Leber’s congenital amaurosis, this finding, that horizontal
cells are necessary for the normal survival of photoreceptor cells,
is novel and significant,” says Mu. “Many retinal
diseases are manifested by the degeneration of photoreceptor
cells.”
This finding was unexpected, Mu explains, because most
investigations into the degeneration of photoreceptor cells have
involved genes that directly affect photoreceptor cell
development.
“People haven’t been looking at horizontal
cells,” he says. “We didn’t think that
they’d be involved in photoreceptor cell degradation.
“With this finding, we have discovered that retinal
horizontal cells are required for maintaining the integrity of the
retina and that their deficiency can lead to retinal
degradation,” explains Mu.
He notes that in most cases where photoreceptor cells die,
it’s because they are somehow defective.
“But in this case, the photoreceptor cells are fine in the
beginning, so the death of the photoreceptor cells is a secondary
affair that is somehow driven by the deficiency in horizontal
cells,” he says.
UB co-author Steven J. Fliesler, PhD, Meyer H. Riwchun Endowed
Chair Professor, vice-chair and director of research in the
Department of Ophthalmology and professor in the Department of
Biochemistry, notes that this finding could open up a new area of
study.
“One scenario we have speculated upon is that there are
important supportive interactions between horizontal cells and
photoreceptors that are required to maintain photoreceptor function
and viability,” Fliesler says. “When horizontal cells
are blocked from being formed -- the immediate consequence of
knocking out Onecut1 -- the photoreceptors don't get what they need
to survive, so they degenerate and die later on.”
The majority of the research was conducted in the UB Department
of Ophthalmology/Ross Eye Institute and the developmental genomics
group at UB’s New York State Center of Excellence in
Bioinformatics and Life Sciences.
First author on the paper is Fuguo Wu of UB. Other UB co-authors
are Renzhong Li, Tadeusz J. Kaczynski, Darshan Sapkota. Additional
co-authors are Yumiko Umino and Eduardo Solessio of SUNY Upstate
Medical University, Shengguo Li and Mengqing Xiang of the
University of Medicine and Dentistry of New Jersey, David M. Sherry
of the University of Oklahoma Health Sciences Center and Maureen
Gannon of Vanderbilt University Medical Center.
Mu, Fliesler and Solessio also are faculty members of the SUNY
Eye Institute, a SUNY-wide eye research consortium.
The work was supported by the Whitehall Foundation, the National
Eye Institute, the SUNY/RF Research Collaboration Fund, Research to
Prevent Blindness, the Oklahoma Center for the Advancement of
Science and Technology, the Lions of Central New York, and
resources and facilities provided by the Veterans Administration
Western NY Healthcare System.