College of Optometry Department
Office: 2143J Davis Armistead Building
Contact: email@example.com - (713) 743-1952
Education: Ph.D., Cell Developmental and Neural Biology; University of Michigan
Transcriptional and epigenetic regulation of gene expression; retinal stem cell biology; molecular genetics of retinal development and differentiation.
During development, distinct and often dynamic patterns of gene expression are critical for cell fate specification and differentiation as well as regulating the patterns of the synatpic connections of retinal neurons. The long term goal of my research is to understand the transcriptional mechanisms that establish and maintain spatial and cell-specific patterns of gene expression in retinal neurons during development, differentiation and synaptogenesis. We are pursuing two main lines of research. First, we are studying the cellular mechanisms regulating neuronal differentiation by glial-derived retinal stem cells. Second, we are characterizing the molecular mechanisms controlling expression of a family of signaling molecules, the Ephrin receptors (Eph), that are known to play a critical role in patterning the connections of retinal ganglion cells in the brain.
Retinal Stem Cell Biology Some species, notably teleost fish and amphibians, are able to regenerate retinal neurons following injury. In contrast, in mammals there is no spontaneous retinal regeneration. In fish, the stem cells present in the inner retina arise from the Muller glia therefore, there is considerable interest in the neurogenic capacity of Muller glia from the mammalian retina. We have isolated a novel cell line of Muller glia from post-natal mice that have stem cell characteristics in vitro. We have found that culturing cells in three-dimensional hydrogel cultures increases expression of specific genes that expressed in differentiated retinal neurons in the mature retina. Using combinatorial treatment with specific growth factors, over-expression of developmentally important transcription factors and targeted gene knockdown, we are identifying mechanisms that will suppress glial identity and enhance the neuronal potential of these cells. The long term goal is to generate sheets of stem cells that are biased to generate specific cell types that can be used for transplantation into the retina to replace neurons that are lost as a result of degenerative retinal disease.
Transcriptional Regulation of Eph Receptor Expression Eph receptors are tyrosine kinase receptors involved in diverse patterning events during embryogenesis. In the developing retina, gradients of Eph receptors along the nasal/temporal and dorsal/ventral axes specifies the position of retinal ganglion cells within the retina. Eph receptors on the growth cones of the retinal ganglion cells respond to counter gradients of ligands in visual centers in the brain and patterns the spatial organization of retinal ganglion cell terminals. In order to regenerate the optic nerve in degenerative diseases such as glaucoma, we need to first understand how to generate new ganglion cells, and then how to direct them to re-establish the appropriate patterns of connectivity within the brain. To address this, we have cloned the promoters of four Eph receptors that are expressed in the retina are studying the role of specific transcriptional factors and changes in chromatin structure including DNA methylation on promoter activity. A new and related initiative we are undertaking is to characterize the global patterns of DNA methylation and gene expression in retinal ganglion cells and how these change during the disease progression in a mouse model of inherited glaucoma.
Some of the techniques used in these studies include tissue culture, in vitro promoter activation assays, histology, immunostaining and in situ hybridization, light and fluorescence microscopy; confocal microscopy and molecular biological methods such as Northerns, Southerns, Westerns, gel mobility shift assays, cloning, quantitative RT-PCR, DNAseI footprinting, chromatin immunoprecipitation, bisulfite sequencing, transgenic animals, in vitro transcription and translation, site directed mutagenesis.
- Wang, M, Frishman LJ, Otteson DC (2009) Intracellular Delivery of Proteins into Mouse Müller Glia Cells in vitro and in vivo using Pep-1 Transfection Reagent. Journal of Neuroscience Methods 177:403-419.
- Mojumder, DK, Frishman LJ, Otteson DC, Sherry DM (2007) Voltage-gated Sodium Channel Alpha Subunits NaV1.1, NaV1.2 and NaV1.6 in the Distal Mammalian Retina. Molecular Vision Electronic Resource 13:2163-82.
- Otteson DC, Tsujikawa T, Gunatilaka T, Malicki J, Zack DJ (2005) Genomic Organization of Zebrafish Cone rod Homeobox Gene and Exclusion as a Candidate Gene for Retinal Degeneration in niezerka and mikre oko. Molecular Vision Electronic Resource. 11: 986-995.
- Otteson DC, Lai H, Liu YH, Zack DJ (2005) Zinc-finger Domains of the Transcriptional Repressor KLF15 Bind Multiple Sites in Rhodopsin and IRBP Promoters Including the CRS-1 and G-rich Repressor Elements. BMC Molecular Biology 17:15 PMID: 15963234.
- Kerrison JB, Lewis RN, Otteson DC, Zack DJ (2005) Bone Morphogenetic Proteins Promote Neurite Outgrowth in Retinal Ganglion Cells. Molecular Vision Electronic Resource. 11:208-15.
- Otteson DC, Liu Y, Lai H, Wang C, Gray S, Jain MK, Zack DJ (2004) Kruppel-like Factor 15, a Zinc finger Transcriptional Regulator, Represses the Rhodopsin and Interphotoreceptor Retinoid binding Protein Promoters. Investigative Ophthalmology Visual Science. 45(8):2522-30.
- Otteson, DC, PF Hitchcock (2003) Stem Cells in the Teleost Retina: Persistent Neurogenesis and Injury-induced Regeneration. Vision Research. 43(8): 927-936.
- Otteson DC, Cirenza PF, Hitchcock PF (2002) Persistent Neurogenesis in the Teleost Retina Evidence for Regulation By the Growth Hormone/Insulin-like Growth Factor I Axis. Mechanisms of Development. 117(1-2):137-49.
- Otteson DC, D'Costa AR, Hitchcock PF (2001) Putative Stem Cells and the Lineage of Rod Photoreceptors in the Mature Retina of the Goldfish. Developmental Biology. 232(1):62-76.
- Otteson DC, Shelden E, Jones JM, Kameoka J, Hitchcock PF (1998) Pax2 Expression and Retinal Morphogenesis in the Normal and Krd Mouse. Developmental Biology. 193(2):209-24.