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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, 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 dissect the roles of eyes absent and sine oculis, two conserved genes controlling
retinal determination and differentiation. We are using ChIP-Seq to identify direct targets of the Sine oculis homeobox transcription factor as well as several
other key proteins required for normal retinal development. In addition, we are using a novel genomic rescue strategy to definitively dissect the in vivo
function of several conserved domains in these proteins. Finally, we are using transcriptional regulation of eyes absent as a paradigm for studying the
relationship between chromatin remodeling and developmental regulation of this key retinal gene.
In our second approach, we are using mouse knockout and knockin technology to determine the function of several new genes whose expression is specifically
enriched in the retina during development. These genes include a histone demethylase, a protein phosphatase, a phospholipase, a protein kinase, and a
transcription factor. Germline transmission of several knockout constructs have already been generated and we expect to have targeted knockouts of all genes
within the next year. Complete functional studies will be conducted and several new projects are 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 are 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. Chen, Lupski, and 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. Mouse models will be created for each new disease gene identified.
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.
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)
Pepple KL, Anderson AE, Frankfort BJ, Mardon G (2007) A genetic screen in Drosophila for genes interacting with senseless during neuronal
development identifies the importin moleskin. Genetics 175:125-141.
Davis RJ, Harding M, Moayedi Y, Mardon G (2008) Mouse Dach1 and Dach2 are redundantly required for Müllerian duct development.
Genesis 46:205-213.
Pepple KL, Atkins M, Venken K, Wellnitz K, Harding M, Frankfort B, Mardon G (2008) Two-step selection of a single R8 photoreceptor: a bistable
loop between senseless and rough locks in R8 fate. Development 135:4071-4079.
Li Y, Wang H, Peng J, Gibbs RA, Lewis RA, Lupski JR, Mardon G, Chen R (2008) Mutation survey of known LCA Genes and loci in the Saudi Arabian
population. Investigative Ophthalmology and Visual Science, Oct 20 online, PMID: 18936139.
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.edu
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