Project Details
Description
Abstract
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 TGFβ, 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/β-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
Status | Active |
---|---|
Effective start/end date | 5/1/13 → 8/31/24 |
Funding
- National Eye Institute: $407,400.00
- National Eye Institute: $419,584.00
- National Eye Institute: $56,746.00
- National Eye Institute: $417,500.00
- National Eye Institute: $409,150.00
- National Eye Institute: $272,767.00
- National Eye Institute: $360,754.00
- National Eye Institute: $417,500.00
- National Eye Institute: $136,383.00
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