Photo of Constance L. Cepko,  PhD

Constance L. Cepko, PhD

Harvard Medical School

Harvard Medical School
Phone: (617) 432-7618
Fax: (617) 432-7595


cepko@genetics.med.harvard.edu

Constance L. Cepko, PhD

Harvard Medical School

EDUCATIONAL TITLES

  • Bullard Professor of Genetics and Neuroscience, Genetics, Harvard Medical School
  • Professor, Ophthalmology, Harvard Medical School

DF/HCC PROGRAM AFFILIATION

Research Abstract

Connie Cepko

Brief Description:

Development, degeneration, and circuitry of the vertebrate retina

We are interested in the mechanisms that direct development 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 have used genomics approaches to determine genes that are candidates for a role in cell fate determination. We are now trying to determine how the retina uses this large repetoire of genes to form this complex tissue of >60 neuronal cell types. To aid in these studies, we also 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 this end, and more generally to discover the circuitry of CNS neurons, we have recently developed novel viral vectors which move transsynaptically in vivo. These vectors can be modified to transmit either retrogradely or anterogradely, and can be used to transduce a variety of genes, encoding fluorescent proteins, ion channels, or calcium indicators. We are interested in their applications in neuroscience, as well as what they can tell us about how viruses transmit among neurons. We are also using them to learn more about retinal circuitry.

We are also interested in the mechanisms that lead to the death of photoreceptors in the many inherited forms of human blindness. 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. 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.

 

Publications

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  • Xiong W, MacColl Garfinkel AE, Li Y, Benowitz LI, Cepko CL. NRF2 promotes neuronal survival in neurodegeneration and acute nerve damage. J Clin Invest 2015; 125:1433-45. PubMed
  • Mundell NA, Beier KT, Pan YA, Lapan SW, Göz Aytürk D, Berezovskii VK, Wark AR, Drokhlyansky E, Bielecki J, Born RT, Schier AF, Cepko CL. Vesicular stomatitis virus enables gene transfer and transsynaptic tracing in a wide range of organisms. J Comp Neurol 2015. PubMed
  • Mizeracka K, Trimarchi JM, Stadler MB, Cepko CL. Analysis of gene expression in wild-type and Notch1 mutant retinal cells by single cell profiling. Dev Dyn 2013; 242:1147-59. PubMed
  • Tang JC, Szikra T, Kozorovitskiy Y, Teixiera M, Sabatini BL, Roska B, Cepko CL. A nanobody-based system using fluorescent proteins as scaffolds for cell-specific gene manipulation. Cell 2013; 154:928-39. PubMed
  • Mizeracka K, DeMaso CR, Cepko CL. Notch1 is required in newly postmitotic cells to inhibit the rod photoreceptor fate. Development 2013; 140:3188-97. PubMed
  • Emerson MM, Surzenko N, Goetz JJ, Trimarchi J, Cepko CL. Otx2 and Onecut1 promote the fates of cone photoreceptors and horizontal cells and repress rod photoreceptors. Dev Cell 2013; 26:59-72. PubMed
  • Jiang H, Wang L, Beier KT, Cepko CL, Fekete DM, Brigande JV. Lineage analysis of the late otocyst stage mouse inner ear by transuterine microinjection of a retroviral vector encoding alkaline phosphatase and an oligonucleotide library. PLoS ONE 2013; 8:e69314. PubMed
  • Beier KT, Saunders AB, Oldenburg IA, Sabatini BL, Cepko CL. Vesicular stomatitis virus with the rabies virus glycoprotein directs retrograde transsynaptic transport among neurons in vivo. Front Neural Circuits 2013; 7:11. PubMed
  • Beier K, Cepko C. Viral tracing of genetically defined neural circuitry. 2012. PubMed
  • Beier KT, Samson ME, Matsuda T, Cepko CL. Conditional expression of the TVA receptor allows clonal analysis of descendents from Cre-expressing progenitor cells. Dev Biol 2011. PubMed
  • Huynh MA, Ikeuchi Y, Netherton S, de la Torre-Ubieta L, Kanadia R, Stegmüller J, Cepko C, Bonni S, Bonni A. An Isoform-Specific SnoN1-FOXO1 Repressor Complex Controls Neuronal Morphogenesis and Positioning in the Mammalian Brain. Neuron 2011; 69:930-44. PubMed
  • Cronican JJ, Thompson DB, Beier KT, McNaughton BR, Cepko CL, Liu DR. Potent delivery of functional proteins into Mammalian cells in vitro and in vivo using a supercharged protein. ACS Chem Biol 2010; 5:747-52. PubMed
  • Rompani SB, Cepko CL. A common progenitor for retinal astrocytes and oligodendrocytes. J Neurosci 2010; 30:4970-80. PubMed
  • Kanadia RN, Cepko CL. Alternative splicing produces high levels of noncoding isoforms of bHLH transcription factors during development. Genes Dev 2010; 24:229-34. PubMed
  • Bienvenu F, Jirawatnotai S, Elias JE, Meyer CA, Mizeracka K, Marson A, Frampton GM, Cole MF, Odom DT, Odajima J, Geng Y, Zagozdzon A, Jecrois M, Young RA, Liu XS, Cepko CL, Gygi SP, Sicinski P. Transcriptional role of cyclin D1 in development revealed by a genetic-proteomic screen. Nature 2010; 463:374-8. PubMed
  • Billings NA, Emerson MM, Cepko CL. Analysis of thyroid response element activity during retinal development. PLoS ONE 2010; 5:e13739. PubMed
  • Samson M, Emerson MM, Cepko CL. Robust marking of photoreceptor cells and pinealocytes with several reporters under control of the Crx gene. Dev Dyn 2009; 238:3218-25. PubMed
  • Trimarchi JM,Cho SH,Cepko CL. Identification of genes expressed preferentially in the developing peripheral margin of the optic cup. Dev Dyn 2009; 238:2327-9. PubMed
  • Jadhav AP,Roesch K,Cepko CL. Development and neurogenic potential of Muller glial cells in the vertebrate retina. Prog Retin Eye Res 2009; 28:249-62. PubMed
  • 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; 106:9495-500. PubMed
  • Dyer MA,Martins R,da Silva Filho M,Muniz JA,Silveira LC,Cepko CL,Finlay BL. Developmental sources of conservation and variation in the evolution of the primate eye. Proc Natl Acad Sci U S A 2009; 106:8963-8. PubMed
  • Chen B,Cepko CL. HDAC4 regulates neuronal survival in normal and diseased retinas. Science 2009; 323:256-9. PubMed
  • Punzo C,Kornacker K,Cepko CL. Stimulation of the insulin/mTOR pathway delays cone death in a mouse model of retinitis pigmentosa. Nat Neurosci 2008; 12:44-52. PubMed
  • Kanadia RN,Clark VE,Punzo C,Trimarchi JM,Cepko CL. Temporal requirement of the alternative-splicing factor Sfrs1 for the survival of retinal neurons. Development 2008; 135:3923-33. PubMed
  • Kim DS,Matsuda T,Cepko CL. A core paired-type and POU homeodomain-containing transcription factor program drives retinal bipolar cell gene expression. J Neurosci 2008; 28:7748-64. PubMed
  • Lagali PS, Balya D, Awatramani GB, Munch TA, Kim DS, Busskamp V, Cepko CL, Roska B. Light-activated channels targeted to ON bipolar cells restore visual function in retinal degeneration. Nat Neurosci 2008; 11:667-75. PubMed
  • Roesch K, Jadhav AP, Trimarchi JM, Stadler MB, Roska B, Sun BB, Cepko CL. The transcriptome of retinal Muller glial cells. J Comp Neurol 2008; 509:225-238. PubMed
  • Damiani D, Alexander JJ, O'Rourke JR, McManus M, Jadhav AP, Cepko CL, Hauswirth WW, Harfe BD, Strettoi E. Dicer inactivation leads to progressive functional and structural degeneration of the mouse retina. J Neurosci 2008; 28:4878-87. PubMed
  • Punzo C, Cepko CL. Ultrasound-guided in utero injections allow studies of the development and function of the eye. Dev Dyn 2008; 237:1034-42. PubMed
  • Kim DS, Ross SE, Trimarchi JM, Aach J, Greenberg ME, Cepko CL. Identification of molecular markers of bipolar cells in the murine retina. J Comp Neurol 2008; 507:1795-1810. PubMed
  • Rompani SB, Cepko CL. Retinal progenitor cells can produce restricted subsets of horizontal cells. Proc Natl Acad Sci U S A 2007; 105:192-7. PubMed
  • Trimarchi JM,Harpavat S,Billings NA,Cepko CL. Thyroid hormone components are expressed in three sequential waves during development of the chick retina. BMC Dev Biol 2008; 8:101. PubMed
  • Morrow EM, Chen CM, Cepko CL. Temporal order of bipolar cell genesis in the neural retina. Neural Develop 2008; 3:2. PubMed
  • Trimarchi JM, Stadler MB, Cepko CL. Individual retinal progenitor cells display extensive heterogeneity of gene expression. PLoS ONE 2008; 3:e1588. PubMed
  • Matsuda T, Cepko CL. Analysis of gene function in the retina. Methods Mol Biol 2008; 423:259-78. PubMed
  • Corbo JC, Myers CA, Lawrence KA, Jadhav AP, Cepko CL. A typology of photoreceptor gene expression patterns in the mouse. Proc Natl Acad Sci U S A 2007; 104:12069-74. PubMed
  • Trimarchi JM, Stadler MB, Roska B, Billings N, Sun B, Bartch B, Cepko CL. Molecular heterogeneity of developing retinal ganglion and amacrine cells revealed through single cell gene expression profiling. J Comp Neurol 2007; 502:1047-65. PubMed
  • Viney TJ, Balint K, Hillier D, Siegert S, Boldogkoi Z, Enquist LW, Meister M, Cepko CL, Roska B. Local retinal circuits of melanopsin-containing ganglion cells identified by transsynaptic viral tracing. Curr Biol 2007; 17:981-8. PubMed
  • Chen B, Cepko CL. Requirement of histone deacetylase activity for the expression of critical photoreceptor genes. BMC Dev Biol 2007; 7:78. PubMed
  • Hsiau TH, Diaconu C, Myers CA, Lee J, Cepko CL, Corbo JC. The cis-regulatory logic of the mammalian photoreceptor transcriptional network. PLoS ONE 2007; 2:e643. PubMed
  • Cho SH, Cepko CL. Wnt2b/{beta}-catenin-mediated canonical Wnt signaling determines the peripheral fates of the chick eye. Development 2006; 133:3167-77. PubMed
  • Jadhav AP, Mason HA, Cepko CL. Notch 1 inhibits photoreceptor production in the developing mammalian retina. Development 2006; 133:913-23. PubMed
  • Corbo JC, Cepko CL. A hybrid photoreceptor expressing both rod and cone genes in a mouse model of enhanced S-cone syndrome. PLoS Genet 2005; 1:e11. PubMed
  • Blackshaw S, Harpavat S, Trimarchi J, Cai L, Huang H, Kuo WP, Weber G, Lee K, Fraioli RE, Cho SH, Yung R, Asch E, Ohno-Machado L, Wong WH, Cepko CL. Genomic analysis of mouse retinal development. PLoS Biol 2004; 2:E247. PubMed
  • 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; 36:351-60. PubMed
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