Professor, Baylor College of Medicine
B.S., Haverford College, Haverford, PA, 1980
Ph.D., Massachusetts Institute of Technology, Whitehead Institute, Cambridge, 1990
Postdoc, University of California, Berkeley, 1990-94
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.
Frankfort BJ, Mardon G (2004) Senseless represses nuclear transduction of Egfr pathway activation. Development 131:563-570.
Pesah Y, Pham T, Burgess H, Middlebrooks B, Verstreken P, Zhou Y, Harding M, Bellen H, Mardon G (2004) Drosophila parkin mutants have decreased mass and cell size and increased sensitivity to oxygen radical stress. Development 131:2183-2194.
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.
Pesah Y, Burgess H, Middlebrooks B, Ronningen K, Prosser J, Tirunagaru V, Zysk J, Mardon G (2005) Whole-mount analysis reveals normal numbers of dopaminergic neurons following misexpression of alpha-Synuclein in Drosophila. Genesis 41:154-159.
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)
Davis RJ, Pesah YI, Harding M, Paylor R, Mardon G (2006) Mouse Dach2 mutants do not exhibit gross defects in eye development or brain function. Genesis 44:84-92
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.
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.
Atkins M, Mardon G (2009) Signaling in the third dimension: the peripodial epithelium in eye disc development. Developmental Dynamics 238:2139-2148.
Anderson AE, Karandikar UC, Pepple KL, Chen Z, Bergmann A, Mardon G (2011) The enhancer of trithorax and polycomb gene Caf1/p55 is essential for cell survival and patterning in Drosophila development. Development 138:1957-1966.
Jiang Y, Scott KL, Kwak SJ, Chen R, Mardon G (2011) Sds22/PP1 links epithelial integrity and tumor suppression via regulation of myosin II and JNK signaling. Oncogene 30:3248-3260.
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