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Molecular mechanisms controlling retinal development
The primary goal of our research is to understand molecular mechanisms of retinal development with the ultimate goal
of improving our ability diagnose, prevent, and treat human retinal disease. To this end, we are using three approaches, all in
collaboration with Dr. Rui Chen, also in the Department of Molecular and Human Genetics.
The first two approaches use the mouse Mus musculus and the fruit fly Drosophila melanogaster as animal model systems to
identify and determine the function of conserved genes required for normal retinal development. The third approach is to map new human
retinal disease genes. In spite of substantial differences between vertebrate and insect retinal morphology, genetic mechanisms of
retinal development have been conserved for more than 500 million years. Thus, study of the molecular and genetic pathways controlling
Drosophila eye development has provided a valuable set of tools with which to decipher the development and function of the
vertebrate retina. Our main Drosophila project uses a combinatorial approach of genetics, genomics, and computational biology
to identify new genes required for normal retinal development. Using a large set of microarray data, we have identified more than 100
new genes that are likely to be involved in eye development and/or function. We are systematically deleting each of these genes and
then carefully analyzing the loss-of-function phenotypes associated with each deletion using a full array of molecular, genetic,
biochemical, and bioinformatic techniques. Many of these newly identified genes have produced striking retinal phenotypes and are
currently under intense investigation. Many new projects are available.
In our second approach, we are using mouse knockout and knockin technology to determine the function of eight new genes whose
expression is specifically enriched in the retina during development. Homologs of several of these genes are also being studied in
zebrafish. These genes include a transcription factor, a protein phosphatase, a phospholipase, a putative calcium channel, a protein
kinase, and a transportin. Several knockout constructs have already been generated and electroporated into ES cells and we expect to
have targeted knockouts of all eight genes within the next year. Complete functional studies will be conducted and several new projects
are therefore available.
Our third project is to map new human disease genes associated with Leber Congenital Amaurosis (LCA), the most common cause of
blindness in children. While there 12 genes known to be associated with LCA these account for only about 70% of all cases. Therefore,
several new loci remain to be identified. In collaboration with Drs. James Lupski and Richard Lewis, we are using whole genome linkage
studies to map new LCA genes in 29 families. We have already identified one new putative disease gene and expect several more in the
near future. Several new projects are possible in this area as well.
Selected Publications
Chen R, Amoui M, Zhang Z, Mardon G (1997) Dachshund and eyes absent proteins form a complex and function
synergistically to induce ectopic eye development in Drosophila. Cell 91:893-903.
Frankfort BJ, Nolo R, Zhang Z, Bellen H, Mardon G (2001) senseless repression of rough is
required for R8 photoreceptor differentiation in the developing Drosophila eye. Neuron 32:403-414.
Frankfort BJ, Mardon G (2002) R8 development in the Drosophila eye: a paradigm for neural selection and differentiation.
Development 129:1295-1306.
Pappu KS, Chen R, Middlebrooks BW, Woo C, Heberlein U, Mardon G (2003) Mechanism of hedgehog signaling during
Drosophila eye development. Development 130:3053-3062.
Frankfort BJ, Mardon G (2004) Senseless represses nuclear transduction of Egfr pathway
activation. Development 131:563-570.
Pappu KS, Mardon G (2004) Genetic control of retinal specification and determination in Drosophila.
International Journal of Developmental Biology 48:913-924.
Chen R, Mardon G (2005) Keeping an eye on the fly genome. Developmental Biology. 282:285-293.
Pappu KS, Ostrin EJ, Middlebrooks BW, Sili BT, Chen R, Atkins MR, Gibbs R, Mardon G (2005) Dual regulation and redundant
function of two eye-specific enhancers of the Drosophila retinal determination gene dachshund. Development
132:2895-2905.
Ostrin EJ*, Li Y*, Hoffman K, Liu J, Wang K, Zhang L, Mardon G, Chen R (2006) Genome-wide identification of direct targets of
the Drosophila retinal determination protein Eyeless. Genome Research 16:466-476. (* equal contribution)
Contact Information
- Graeme Mardon, Ph.D.
- Department of Pathology
- Baylor College of Medicine
- One Baylor Plaza T222
- Houston, Texas 77030, U.S.A.
- Tel: (713) 798-8731
- Fax: (713) 798-3359
- E-mail: gmardon@bcm.tmc.edu
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