Congenital retina abnormalities such as retinal degenerative diseases cause varying degrees of irreversible vision loss in millions of people worldwide. Although recent advances in our understanding of retinal development have facilitated the use of screening protocols to detect mutations in genes associated with those ocular diseases, no therapeutic approach is yet available. A conserved network of transcription factors is essential for eye formation. The homeobox-containing gene Six3 is one of the members of that complex network that regulates visual system development. Conditional removal of Six3 from the developing mouse eye field is sufficient to arrest NR specification;a result demonstrating the critical role of Six3 during vertebrate retina development. The work proposed in this application builds on our previous findings and our generated mouse models to expand our knowledge about the processes leading to the formation of the visual system.

Public Health Relevance

Recent advances using embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) suggest that one day cell-replacement therapy will be used to treat these ocular diseases. A prerequisite to achieving this goal is to better understand the regulatory cascades and signaling pathways that control normal retina development. This knowledge will help us to better understand the pathogenesis of ocular diseases and provide the essential framework necessary to design approaches that will facilitate future efforts aimed toward controlling the differentiation of ESCs and iPSCs, in vivo and in vitro, into retina cells.

National Institute of Health (NIH)
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Greenwell, Thomas
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St. Jude Children's Research Hospital
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Lavado, Alfonso; Oliver, Guillermo (2014) Jagged1 is necessary for postnatal and adult neurogenesis in the dentate gyrus. Dev Biol 388:11-21
Lavado, Alfonso; Oliver, Guillermo (2011) Six3 is required for ependymal cell maturation. Development 138:5291-300
McGovern, Suzanne; Pan, Jie; Oliver, Guillermo et al. (2010) The role of hypoxia and neurogenic genes (Mash-1 and Prox-1) in the developmental programming and maturation of pulmonary neuroendocrine cells in fetal mouse lung. Lab Invest 90:180-95
Lavado, Alfonso; Lagutin, Oleg V; Oliver, Guillermo (2008) Six3 inactivation causes progressive caudalization and aberrant patterning of the mammalian diencephalon. Development 135:441-50
Geng, Xin; Lavado, Alfonso; Lagutin, Oleg V et al. (2007) Expression of Six3 Opposite Strand (Six3OS) during mouse embryonic development. Gene Expr Patterns 7:252-7
Lim, Jae H; Booker, Anne B; Luo, Ting et al. (2005) AP-2alpha selectively regulates fragile X mental retardation-1 gene transcription during embryonic development. Hum Mol Genet 14:2027-34
Purcell, Patricia; Oliver, Guillermo; Mardon, Graeme et al. (2005) Pax6-dependence of Six3, Eya1 and Dach1 expression during lens and nasal placode induction. Gene Expr Patterns 6:110-8
Lagutin, Oleg V; Zhu, Changqi C; Kobayashi, Daisuke et al. (2003) Six3 repression of Wnt signaling in the anterior neuroectoderm is essential for vertebrate forebrain development. Genes Dev 17:368-79
Wigle, Jeffrey T; Harvey, Natasha; Detmar, Michael et al. (2002) An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype. EMBO J 21:1505-13
Burke, Zoe; Oliver, Guillermo (2002) Prox1 is an early specific marker for the developing liver and pancreas in the mammalian foregut endoderm. Mech Dev 118:147-55

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