The long-term goal of this project is to elucidate the molecular regulation of photoreceptor production in the vertebrate retina. This knowledge is imperative to the development of effective stem cell-based photoreceptor replacement therapies. Much needs to be learned about the identities of the genes involved and how they contribute to the selection of the photoreceptor fate from among the other options. Studies during the previous funding period identified neuroD as an instrumental player in photoreceptor differentiation, in a transcriptional pathway of ngn2->neuroD->RaxL. In this pathway, ngn2 functions in multipotent progenitors and its downstream genetic targets include neuroD; neuroD elicits a photoreceptor development program, including the expression of homeobox gene RaxL. In this application we will test the hypothesis that photoreceptor production employs ngn1 at a key step between ngn2 and neuroD.
Aim 1 examines whether ngn1 is expressed at the right place and the right time to be a major gene in leading progenitors to the photoreceptor path.
Aim 2 investigates whether ngn1 expressly steers progenitors to the photoreceptor path and, thus, leads exclusively to photoreceptor production.
Aim 3 determines whether ngn1 is required for photoreceptor production.
Aim 4 addresses how ngn1 genetically relates to ngn2 and neuroD during photoreceptor production. These studies will be carried out with a battery of techniques from molecular biology, cell biology, developmental biology, and genetics. This project promises to shed light on the transcriptional regulation governing photoreceptor production. Furthermore, it bears clinical implications. The identification of key genetic players in photoreceptor production will capacitate efficient in vitro or in vivo photoreceptor generation for studies with therapeutic goals. These studies are timely in this era of heightened interest in stem cell research for replacement therapies. ? ? ?
|Yan, Run-Tao; He, Li; Zhan, Wenjie et al. (2015) Induction of ectopic retina-like tissue by transgenic expression of neurogenin. PLoS One 10:e0116171|
|Wang, Shu-Zhen; Yan, Run-Tao (2014) The Retinal Pigment Epithelium: a Convenient Source of New Photoreceptor cells? J Ophthalmic Vis Res 9:83-93|
|Yan, Run-Tao; Li, Xiumei; Wang, Shu-Zhen (2013) Photoreceptor-like cells in transgenic mouse eye. Invest Ophthalmol Vis Sci 54:4766-75|
|Yan, Run-Tao; Li, Xiumei; Huang, Jian et al. (2013) Photoreceptor-like cells from reprogramming cultured mammalian RPE cells. Mol Vis 19:1178-87|
|Ma, Wenxin; Wang, Shu-Zhen (2012) Fate tracing of neurogenin2-expressing cells in the mouse retina using CreERýýý: LacZ. Methods Mol Biol 884:141-52|
|Wang, Shu-Zhen; Yan, Run-Tao (2012) Chick retinal pigment epithelium transdifferentiation assay for proneural activities. Methods Mol Biol 884:201-9|
|Yan, Run-Tao; Wang, Shu-Zhen (2012) Production of high-titer RCAS retrovirus. Methods Mol Biol 884:193-9|
|Yan, Run-Tao; Liang, Lina; Ma, Wenxin et al. (2010) Neurogenin1 effectively reprograms cultured chick retinal pigment epithelial cells to differentiate toward photoreceptors. J Comp Neurol 518:526-46|
|Li, Xiumei; Ma, Wenxin; Zhuo, Yehong et al. (2010) Using neurogenin to reprogram chick RPE to produce photoreceptor-like neurons. Invest Ophthalmol Vis Sci 51:516-25|
|Wang, Shu-Zhen; Ma, Wenxin; Yan, Run-Tao et al. (2010) Generating retinal neurons by reprogramming retinal pigment epithelial cells. Expert Opin Biol Ther 10:1227-39|
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