The long-term goal of this research program is to elucidate the fundamental mechanisms underlying mammalian retinal development through molecularly dissecting the roles of transcription factors and signal transduction molecules. In the adult retina, the neuroretina, retinal pigment epithelium, ciliary body, and iris are structurally connected to execute visual functions. During development, the progenitor cells that give rise to these adult retinal tissues are closely related. Morphogenesis of optic cups results in the specification and regionalization of neuroretinal and retinal pigment epithelial progenitor cells in the inner and outer layers of optic cups, respectively. Subsequently, ciliary margin progenitor cells are specified at the periphery of the neuroretina, contributing to the ciliary body and iris. Neuroretinal progenitor cells are multipotent; their coordinated cell proliferation and differentiation produce stratified neuroretina. Abnormalities in any of developmental processes result in retinal blindness. In retinal development, cell specification, cell identity maintenance, and differentiation are tightly regulated by transcription factors, including Six3, Six6, Pax6, Rax, Sox2, and Lhx2. Signaling transduction pathways, including Wnt, FGF, HH, BMP, and TGF?, interplay with the transcription factors. How multipotent neuroretinal progenitor cells are regulated, and how the maintenance of neuroretinal progenitor cells and the specification of ciliary margin progenitors are coordinated along the peripheral-central axis are still critical knowledge gaps. In the previous funding period, we have demonstrated that Six3 and Six6 are jointly required for the maintenance of multipotent neuroretinal progenitor cells in mice. We hypothesize that Six3 and Six6 directly regulate multiple major targets to maintain the identity of multipotent neuroretinal progenitor cells. The hypothesis will be tested using both candidate and unbiased approaches. We will first determine the major targets of Six3 and Six6 in suppressing Wnt/?-catenin signaling to maintain multipotent neuroretinal cell identity (Aim 1), and then elucidate the molecular mechanisms by which Six3 and Six6 jointly suppress ciliary margin cell fate at the far periphery but maintain the multipotency of neuroretinal progenitor cells at the mid periphery in the neuroretina (Aim 2). The proposed studies are built upon our intriguing mouse models as well as unbiased cutting-edge approaches already established in our laboratory. When completed, these studies will provide deeper insights into the molecular and cellular mechanisms of retinal differentiation and uncover therapeutic opportunities for regenerative medicine of the human neuroretina. 1

Public Health Relevance

The NEI Audacious Goal Initiative to regenerate and reconnect damaged retinal neurons via directed cell differentiation or re-programming provides hope for curing retinal degenerations. Accomplishment of the proposed studies will provide deeper insight into the cellular and molecular mechanisms of retinal differentiation and regeneration, moving a step closer to cure degenerative retinal blindness.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology of the Visual System Study Section (BVS)
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Neuhold, Lisa
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Albert Einstein College of Medicine
United States
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Diacou, Raven; Zhao, Yilin; Zheng, Deyou et al. (2018) Six3 and Six6 Are Jointly Required for the Maintenance of Multipotent Retinal Progenitors through Both Positive and Negative Regulation. Cell Rep 25:2510-2523.e4
Liu, Wei; Cvekl, Ales (2017) Six3 in a small population of progenitors at E8.5 is required for neuroretinal specification via regulating cell signaling and survival in mice. Dev Biol 428:164-175
Lowe, Albert; Harris, Raven; Bhansali, Punita et al. (2016) Intercellular Adhesion-Dependent Cell Survival and ROCK-Regulated Actomyosin-Driven Forces Mediate Self-Formation of a Retinal Organoid. Stem Cell Reports 6:743-756
Xie, Qing; McGreal, Rebecca; Harris, Raven et al. (2016) Regulation of c-Maf and ?A-Crystallin in Ocular Lens by Fibroblast Growth Factor Signaling. J Biol Chem 291:3947-58
He, Shuying; Limi, Saima; McGreal, Rebecca S et al. (2016) Chromatin remodeling enzyme Snf2h regulates embryonic lens differentiation and denucleation. Development 143:1937-47
Cvekl, Ales; McGreal, Rebecca; Liu, Wei (2015) Lens Development and Crystallin Gene Expression. Prog Mol Biol Transl Sci 134:129-67
Liu, Wei (2012) Focus on molecules: Wnt8b: a suppressor of early eye and retinal progenitor formation. Exp Eye Res 101:113-4