Children's Hospital Boston




		Constance Cepko, PhD Professor of Genetics Harvard Medical School MRRC Project(s) Cell Fate Determination in the Retina Research Description Major Results We are interested in the mechanisms that direct development of the vertebrate retina. Candidate genes that may be important in retinal development have been isolated using PCR and homology based upon sequences of relevant genes from other systems. More recently, we have used serial analysis of gene expression (SAGE) and to identify cell type specific genes and those that are important for photoreceptor development. To understand the function of these genes, they are transduced in vivo or in vitro using retrovirus vectors, or their activity is reduced through antisense or knock-out approaches. Genes that control the initial formation and pattern of the retina, as well as the differentiation of several cell types, have been isolated and characterized. For example, we isolated Crx, which we found to be a key regulator of the differentiation of photoreceptors. By examining a Crx knock-out mouse using microarrays and SAGE, we identified potential target genes of Crx. Upstream of these genes, we identified a conserved motif that appears to be a binding site for Crx. Many of these genes turn out to be human disease genes and/or photoreceptor-specific genes. We are also studying the regulatory networks in mitotic, multipotent progenitor cells that control the production distinct retinal cell types. The interaction of progenitor cells with environmental cues that affect cell fate choice is also under study using both in vivo and in vitro approaches. Definition of gene expression changes that occur as a result of photoreceptor degeneration is a project that has recently been initiated using genomic approaches. Our hope is to find the mechanisms that lead to the non-autonomous death of cone photoreceptors that occurs in many human diseases Publications Blackshaw S, Kuo WP, Park PJ, Tsujikawa M, Gunnersen JM, Scott HS, Boon WM, Tan SS, Cepko CL. MicroSAGE is highly representative and reproducible but reveals major differences in gene expression among samples obtained from similar tissues. Genome Biol 2003;4(3):R17. Dyer MA, Livesey FJ, Cepko CL, Oliver G. Prox1 function controls progenitor cell proliferation and horizontal cell genesis in the mammalian retina. Nat Genet 2003;34(1):53-8. Harpavat S, Cepko CL. Thyroid hormone and retinal development: an emerging field. Thyroid 2003;13(11):1013-9. Jin Z, Zhang J, Klar A, Chedotal A, Rao Y, Cepko CL, Bao ZZ. Irx4-mediated regulation of Slit1 expression contributes to the definition of early axonal paths inside the retina. Development 2003;130(6):1037-48. Livesey FJ, Young TL, Cepko CL. An analysis of the gene expression program of mammalian neural progenitor cells. Proc Natl Acad Sci U S A 2004;101(5):1374-9. Matsuda T, Cepko CL. Electroporation and RNA interference in the rodent retina in vivo and in vitro. Proc Natl Acad Sci U S A 2004;101(1):16-22. Pignatelli V, Cepko CL, Strettoi E. Inner retinal abnormalities in a mouse model of Leber's congenital amaurosis. J Comp Neurol 2004;469(3):351-9. Young TL, Cepko CL. A role for ligand-gated ion channels in rod photoreceptor development. Neuron 2004;41(6):867-79. Zhang J, Gray J, Wu L, Leone G, Rowan S, Cepko CL, Zhu X, Craft CM, Dyer MA. Rb regulates proliferation and rod photoreceptor development in the mouse retina. Nat Genet 2004. Rowan S, Chen A, Young TL, Fischer DE, Cepko CL. Transdifferentiation of the retina into pigmented cells in ocular retardation mice defines a new function of the homeodomain gene Chx10. Development 2004, in press. See Dr. Cepko's publications via PubMed Contact Information Email: Constance Cepko, PhD Associate Professor of Pediatrics Harvard Medical School/Children’s Hospital Department of Pediatrics (Endocrinology)