Current Research Interests - 2007
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Photoreceptor cell fate determination, regulation of gene expression, and early-onset retinal diseases
In the vertebrate retina, photoreceptors are specialized neurons that convert light into electrical information. Rod photoreceptors are responsible for night vision while cone photoreceptors provide day-light vision, color perception and high visual acuity and constitute a small fraction (3-5%) of photoreceptors in most mammals (including mice and humans). My lab discovered the NRL (neural retina leucine zipper) gene which has now been established as an essential mediator of gene regulation in both developing and mature rod photoreceptors.
Extensive studies by our laboratory showed that NRL interacts with the cone-rod homeobox protein CRX and orphan nuclear receptor NR2E3 to synergistically regulate the expression of rhodopsin and other rod-specific genes. Our research demonstrated that mutations in the human NRL, CRX, and NR2E3 genes are associated with retinal degenerative diseases.
A major exciting finding came from gene knockout studies. The deletion of Nrl in mice (Nrl-/-) resulted in the complete lack of rod function and rod-specific gene expression; instead, there was enhanced S-cone function indicating rods had converted to S-cones. This has provided an excellent model to study rod and cone photoreceptor biology. These mice are now being used by more than 40 different laboratories all over the world.
Using the Nrl-promoter to drive enhanced green fluorescent protein (EGFP) in transgenic mice, we have now accomplished another major feat, i.e., rod precursors can be tagged at birth with GFP (published in PNAS and on the cover). This has allowed us to study the differentiation of photoreceptor regulatory pathways by producing gene profiles of purified rods from normal and mutant mouse retinas.
Microarray profiling, combined with chromatin immunoprecipitation and in silico studies, has led to the identification of numerous direct targets of NRL and candidate genes of photoreceptor diseases. The GFP-tagged rod precursors have been used for transplantation in both normal and degenerative retinas to partly restore photoreceptor function (published in Nature and on the cover).
Recently, we also discovered that both rod and cone photoreceptors are established from a common pool of post-mitotic precursors (published recently in PNAS and on the cover). Expression of NRL in developing cones can convert these to rods. Gene profiles of purified rods and cones from various transgenic strains can now be generated to identify the minimal gene complement of a distinct retinal neuron.