HMS Virology

Virology Faculty Member - Constance Cepko

Constance Cepko

Professor of Genetics

Harvard Medical School
Genetics, NRB, Rm. 360
77 Avenue Louis Pasteur
Boston, MA 02115
Tel: 617-432-7618
Fax: 617-432-7595
Lab Members: 8 postdoctoral fellows, 4 graduate students

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

We are interested in the mechanisms that direct development, connectivity, and degeneration 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 are working to understand the networks of genes involved in several basic developmental processes, such as the choice of cell fate. We are particularly interested in the production of photoreceptor cells, as vision is absolutely dependent upon these cells. We are also very interested in the diversification of the different types of interneurons as these cells form critical elements in retinal circuitry. To aid in these studies, we carry out lineage studies wherein we mark individual progenitor cells in vivo, and analyze the types of neurons produced. Of interest is whether progenitor cells produce cells that are connected in various types of retinal circuits. To examine the connectivity of neurons, we have been developing viral vectors that enable robust marking of cells, in such a way as to reveal many details of their morphology. We are also exploring the use of chimeric viruses that will jump across neuronal connections, or at least closely juxtaposed neurons, to aid in the identification of neuronal circuits. The mechanisms used by such viruses are also under study.

We are also interested in the mechanisms that lead to the death of photoreceptors in the many inherited forms of human blindness. Through examination of gene expression changes that accompany photoreceptor death in murine models of the human diseases, retinitis pigmentosa, we have discovered that the metabolism of cone photoreceptors appears to be stressed to the point that the cells undergo autophagy. We have found that we can slow down the death of these cells through administration of insulin, whereas the death is accelerated if animals are depleted for insulin. In addition, we have found that delivery of the histone deacetylase 4 gene can slow down the autonomous death of mutant rod photoreceptors via stabilization of the hypoxia inducible factor 1 alpha. We are now investigating whether gene therapy approaches that follow from these findings might extend vision in animal models, with the goal of developing a therapy for humans. Adenoviral and AAV vectors are being developed for these purposes.

Last Update: 8/10/2020


For a complete listing of publications click here.



Beier, K.T., Saunders, A.B., Oldenburg, I.A., Sabatini, B.L., Cepko, C.L. Vesicular stomatitis virus with the rabies virus glycoprotein directs retrograde transsynaptic transport among neurons in vivo. Front Neural Circuits 7:11 (2013). PMCID:PMC3566411

Beier, K., Borghuis, B.G., El-Danaf, R.N., Huberman, A.D., Demb, J.B. and Cepko, C.L. Transsynaptic tracing with vesicular stomatitis virus reveals novel retinal circuitry. J. Neurosci. 33(1):35-51 (2013) PMID:23283320, NIHMS:431157

Hafler** BP, Surzenko** N, Beier K, Punzo C, Trimarchi J, Kong J, Cepko CL. Olig2 defines subpopulations of retinal progenitor cells biased towards specific cell fates. Proc Natl Acad Sci 109(20):7882-7887 (2012) PMCID:PMC3356608

Cherry TJ, Trimarchi JM, Stadler MB, Cepko CL. Development and diversification of retinal amacrine interneurons at single cell resolution Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9495-500.

Chen, B and Cepko, C. HDAC4 regulates neuronal survival in normal and diseased retinas. Science, 323(5911):256-259 (2009).

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