Constance L. Cepko, Ph.D.

Professor of Genetics

Harvard Medical School
New Research Building, Room 360
77 Avenue Louis Pasteur
Boston, MA 02115
Tel: 617-432-7618
Fax: 617-432-7595
e-mail:cepko@receptorl.med.harvard.edu
8 postdoctoral fellows, 4 graduate students

Development of the vertebrate central nervous system with an emphasis on the retina.

We are interested in the mechanisms that direct development of the central nervous system (CNS) of vertebrates. We are focussing our studies on the vertebrate retina, a relatively simple and well-characterized area of the CNS. We have used genomics approaches (SAGE and microarrays) to systematically examine gene expression over time during murine retinal development. We have further investigated the cellular specificity of expression patterns by performing in situ hybridization for >1500 genes with dynamic temporal patterns, and by performing gene profiling on single retinal cells. These studies led to the identification of many excellent candidate genes suspected to be important in development, along with many newly-characterized genes that are enriched or specific in their expression to photoreceptor cells. As many disease genes that affect vision have been found to exhibit photoreceptor-specific or enriched expression, these are an excellent set of candidate genes for these diseases. We are also examining gene expression changes that accompany photoreceptor death in murine models of the human diseases, retinitis pigmentosa, cone-rod dystrophy, and macular degeneation.

To understand the function of genes identified in these and other screens, we are using retroviral transduction or electroporation in vivo or in vitro to misexpress genes. We also reduce gene expression using RNAi or knock-out approaches. In vitro culture systems that mimic retinal development have been developed and are being used to investigate the role of the environment. We are also investigating the regulatory sequences that control selected genes using transgenic mice, electroporation, and retroviral transduction, along with in vitro approaches. To complement these studies, we are using computational approaches to tentatively identify genes that are specific to particular cell types, eg. rod photoreceptors.

Genes that control the initial formation and pattern of the retina, as well as the determination and/or differentiation of several cell types, have been isolated and are being characterized in chicks as well as mice.

References:

1. Young TL, Cepko CL. A role for ligand-gated ion channels in rod photoreceptor development. Neuron 41:867-879 (2004)
2. Blackshaw, S, Harpavat, S, Trimarchi, J, Cai, L, Huang, H, Kuo, W, Lee, K, Fraioli, R, Cho, S, Yung, R, Asch, E, Wong, W, Ohno-Machado, L, Weber, G,, Cepko, C.L. Genomic Analysis of Mouse Retinal Development. PLoS Biology 2(9):E247 (2004)
3. Young, T.L., Matsuda, T., and Cepko, C.L. The noncoding RNA taurine upregulated gene 1 is required for differentiation of the murine retina. Curr Biol 15(6):501-512 (2005)