Graeme Mardon, Ph.D.
Professor of Molecular and Human Genetics
Professor, Departments of Neuroscience; Pathology & Immunology; and Ophthalmology; Programs in Integrative Molecular and Biomedical Sciences and Developmental Biology
Co-Director, Graduate Program in Molecular and Human Genetics
Program Director, NIH Training Grant T32 EY07102
B.S., Haverford College, 1980
Ph.D., Massachusetts Institute of Technology, 1990
Postdoc, University of California, Berkeley, 1994
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, much of which is conducted 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 identify and determine the function of 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. In addition, the mouse provides a powerful model system to decipher the function of newly identified human retinal disease genes.
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 highly conserved genes controlling retinal determination and differentiation in both flies and humans. We are using ChIP-Seq and RNA-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 conserved domains of proteins controlling retinal development. 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 collaboration with the Chen lab, we are also mapping new human disease genes associated with Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis (LCA), the most common causes of blindness in children. While there are many genes known to be associated with RP and/or LCA, these account for only about 50 to 70 percent of all cases. Therefore, several new loci remain to be identified. We have acquired a large group of RP and LCA patients and families and we are using these to identify new disease genes. We have already identified one new LCA disease gene (named SPATA7) and will identify several more in the near future. We have also created a mouse knockout model for Spata7 which fully recapitulates the human disease condition. We are using this model to fully dissect the nature of the human disease condition and as a model for conducting gene therapy studies. Mouse knockout models will also be created for other new disease genes we identify to further elucidate their function in vivo.
A Drosophila pupal eye disc over expressing the gene senseless, stained with antibodies to reveal cell membranes (purple) and the R7 and R8 photoreceptors (green).
- Atkins M, Jiang Y, Sansores-Garcia L, Jusiak B, Halder G, Mardon G (2013). Dynamic rewiring of the Drosophila retinal determination network switches its function from selector to differentiation. PLoS Genet. 9(8): e1003731. PubMed PMID: 24009524
- Koenekoop RK, Wang H, Majewski J, Wang X, Lopez I, Ren H, Chen Y, Li Y, Fishman GA, Genead M, Schwartzentruber J, Solanki N, Traboulsi EI, Cheng J, Logan CV, McKibbin M, Hayward BE, Parry DA, Johnson CA, Nageeb M; Finding of Rare Disease Genes (FORGE) Canada Consortium, Poulter JA, Mohamed MD, Jafri H, Rashid Y, Taylor GR, Keser V, Mardon G, Xu H, Inglehearn CF, Fu Q, Toomes C, Chen R (2012). Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration. Nat. Genet. 44(9): 1035-9. PubMed PMID: 22842230
- 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(10): 1957-66. PubMed PMID: 21490066
- 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(29): 3248-60. PubMed PMID: 21399659
- Wang H, den Hollander AI, Moayedi Y, Abulimiti A, Li Y, Collin RW, Hoyng CB, Lopez I, Bray M, Lewis RA, Lupski JR, Mardon G, Koenekoop RK, Chen R (2009). Mutations in SPATA7 cause Leber congenital amaurosis and juvenile retinitis pigmentosa. Am. J. Hum. Genet. 84(3): 380-7. PubMed PMID: 19268277
- 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(24): 4071-9. PubMed PMID: 19004852
- 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(1): 125-41. PubMed PMID: 17110483
- Ostrin EJ*, Li Y*, Hoffman K, Liu J, Zhang L, Mardon G**, Chen R** (2006). Genome-wide identification of direct targets of the Drosophila retinal determination protein Eyeless. Genome Res. 16(4): 466-76. *These authors contributed equally to this work. **These laboratories contributed equally to this work. PubMed PMID: 16533912
- Pappu K, Chen R, Middlebrooks BW, Woo K, Heberlein U, Mardon G (2003). Mechanism of hedgehog signaling during early Drosophila eye development. Development 130(13): 3053-62. PubMed PMID: 12756186
- Frankfort B, 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(3): 403-14. PubMed PMID: 11709152
- 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(7): 893-903. PubMed PMID: 9428513
Awards and Honors
2008: Best Lecturer, 8-Stranded Beta-Barrel Jelly Roll Awards, Baylor College of Medicine
2002 and 2006: James M. Barr Award for Outstanding Retina Research Achievement
2001: Marc Dresden Excellence in Graduate Education Award, Baylor College of Medicine
1999: Brochstein Award for Outstanding Achievement in Retina Research
Graeme Mardon, Ph.D.
Department of Pathology
Baylor College of Medicine
One Baylor Plaza, MS BCM315
Houston, TX, 77030, U.S.A.