Our past research has led to a special interest in
understanding how transcriptional networks and extracellular cues regulate
retinal bipolar cell development and diversity. Ten morphologically
distinct types of bipolar cells mediate the vertical transmission of photoreceptor signals and represent one of the
first stages in which these signals are broken down into separate streams.
We utilize several transgenic approaches in the lab to address questions
relating to the formation and function of retinal bipolar cells. These
approaches allow us to perform loss
and gain of function and a multitude of other studies using conventional
and conditional gene-targeting strategies. We are fully equipped for
confocal microscopy and have an expertise in standard cell and molecular
biology techniques.
How
does transcription factor combinatorial coding shape the formation of
retinal bipolar cells?
The combinatorial code defined by overlapping and
non-overlapping expression of transcription factors is a major determinant
of neuronal cell type diversity. Our published studies have demonstrated
overlapping and non-overlapping roles for Vsx1 and Irx5 in Type 2 and Type 3 cone bipolar
cell development. My lab has
recently shown that the expression of an Irx5
homologue, Irx6, and the bHLH-encoding gene Bhlhb5 (in
collaboration with Lin GanÕs lab), partially overlap with Vsx1 and Irx5. We hypothesize that these
4 genes act within a regulatory network to direct bipolar cell type
formation. The existence of
viable null mutants for each of these genes provides an excellent
opportunity to examine the transcriptional mechanisms underlying bipolar
cell development. We are examining this area using developmental gene
expression studies, phenotypic analyses of single and combined mutants, and
through chromatin immunoprecipitation and other DNA binding assays.
Do
transcription factors play specific roles within the retinal circuitry?
Genetic or acquired defects affecting retinal interneurons
can potentially lead to a wide range of vision impairment. For example,
defects in large populations of bipolar cells could to lead severe visual
impairment or blindness, while defects affecting sub-populations of
interneurons could lead to more subtle and specific defects. The latter is
illustrated by some of our recent work in
collaboration with
Rachel WongÕs
lab demonstrating that the transcription factors Vsx1 and Irx5 are
essential for contrast adaptation in the OFF visual signaling pathway.
Ultimately, it is anticipated that the knowledge gained from this research
will provide the insight necessary to address and effectively treat
inherited vision disorders.
Do
human VSX1
mutations cause corneal dystrophies?
In addition to its role in retinal development, the
homeodomain transcription factor Vsx1 is also associated with the corneal
dystrophies keratoconus and posterior polymorphism dystrophy. Over the last
four years, 8 dominant VSX1 missense mutations associated
with ocular disease have been identified in humans by four independent
research groups (including a study
by Elise HŽon in which
we collaborated). Controversy exists, however, over whether these mutations
are truly disease-causing. Our recent
work has shown that Vsx1 expression is not
detected in the developing or mature cornea. This raises the possibility of
a cell non-autonomous role for VSX1 in human ocular disease.
