scholarly journals Notch signaling represses cone photoreceptor formation through the regulation of retinal progenitor cell states

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Xueqing Chen ◽  
Mark M. Emerson
Keyword(s):  
Notch Signaling ◽  
Progenitor Cells ◽  
Progenitor Cell ◽  
Regulatory Elements ◽  
Primary Role ◽  
Cone Photoreceptor ◽  
Cone Photoreceptors ◽  
Retinal Progenitor Cells ◽  
Retinal Progenitor

AbstractNotch signaling is required to repress the formation of vertebrate cone photoreceptors and to maintain the proliferative potential of multipotent retinal progenitor cells. However, the mechanism by which Notch signaling controls these processes is unknown. Recently, restricted retinal progenitor cells with limited proliferation capacity and that preferentially generate cone photoreceptors have been identified. Thus, there are several potential steps during cone genesis that Notch signaling could act. Here we use cell type specific cis-regulatory elements to localize the primary role of Notch signaling in cone genesis to the formation of restricted retinal progenitor cells from multipotent retinal progenitor cells. Localized inhibition of Notch signaling in restricted progenitor cells does not alter the number of cones derived from these cells. Cell cycle promotion is not a primary effect of Notch signaling but an indirect effect on progenitor cell state transitions that leads to depletion of the multipotent progenitor cell population. Taken together, this suggests that the role of Notch signaling in cone photoreceptor formation and proliferation are both mediated by a localized function of Notch in multipotent retinal progenitor cells to repress the formation of restricted progenitor cells.

scholarly journals Notch signaling represses cone photoreceptor formation through the regulation of retinal progenitor cell states

2020 ◽  
Author(s):  
Xueqing Chen ◽  
Mark M. Emerson
Keyword(s):  
Cell Cycle ◽  
Notch Signaling ◽  
Progenitor Cells ◽  
Progenitor Cell ◽  
State Transitions ◽  
Proliferative Potential ◽  
Primary Role ◽  
Cone Photoreceptor ◽  
Retinal Progenitor Cells ◽  
Retinal Progenitor

AbstractVertebrate cone photoreceptor formation is a multistep process. First, multipotent retinal progenitor cells generate genetically-defined restricted/neurogenic progenitor cells and these cells then divide to preferentially produce cones and horizontal cells. Notch signaling represses cone formation and maintains the proliferative potential of retinal progenitor cells. However, the mechanisms through which it affects these processes are unknown. Here we use cell type specific inhibition of Notch signaling to localize the primary role of Notch signaling during cone genesis to the regulation of restricted retinal progenitor cells from multipotent retinal progenitor cells. Notch signaling inhibition in restricted progenitor cells does not alter the number of cones derived from these cells but does affect horizontal cell development. Cell cycle promotion is not a primary effect of Notch signaling but an indirect effect on progenitor cell state transitions that leads to depletion of the multipotent progenitor cell population. Taken together, this suggests that the roles of Notch in cone photoreceptor formation and cell cycle promotion are both mediated by a localized function in multipotent retinal progenitor cells to repress the formation of restricted progenitor cells.

The Role of VEGF and VEGFR2/Flk1 in Proliferation of Retinal Progenitor Cells in Murine Retinal Degeneration

2007 ◽  
Vol 48 (9) ◽  
pp. 4315 ◽  
Author(s):  
Koji M. Nishiguchi ◽  
Makoto Nakamura ◽  
Hiroki Kaneko ◽  
Shu Kachi ◽  
Hiroko Terasaki
Keyword(s):  
Retinal Degeneration ◽  
Progenitor Cells ◽  
Retinal Progenitor Cells ◽  
Retinal Progenitor

scholarly journals Stimulation of c-Kit+ Retinal Progenitor Cells by Stem Cell Factor Confers Protection Against Retinal Degeneration

2021 ◽  
Author(s):  
Xi Chen ◽  
Shanshan Li ◽  
Xiaoli Liu ◽  
Jingjie Zhao ◽  
Xiufen Yang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Retinal Degeneration ◽  
Progenitor Cells ◽  
Intravitreal Injection ◽  
Stem Cell Factor ◽  
Retinal Ganglion ◽  
Retinal Progenitor Cells ◽  
Retinal Progenitor ◽  
Dark Transition

Abstract Background c-Kit/CD117, expressed in a series of tissue-specific progenitor cells, plays an important role in tissue regeneration and tissue homeostasis. We previously demonstrated that organoid-derived c-Kit+ retinal progenitor cells can facilitate the restoration of degenerated retina. Meanwhile, we have identified a population of endogenous c-Kit+ cells in retinas of adult mouse. However, the exact role of these cells in retinal degeneration remains unclear. Methods Retinal degeneration was induced by intravitreal injection of N-methyl-D-aspartate (NMDA). Two days post NMDA challenge, intravitreal injection of stem cell factor (SCF) was performed. Distribution and abundance of c-Kit+ cells and other retinal cells were evaluated by immunochemistry. Retinal function of treated mice was tested via flash electroretinogram (fERG) and the light/dark transition test. Possible regulatory pathways were evaluated by RNA sequencing. Results NMDA challenge increased the total number of c-Kit+ cells in the retinal ganglion cell layer (GCL), while slightly deregulated the protein level of SCF, which is mainly expressed in Müller cells. Both fERG and light/dark transition tests showed that intravitreal injection of SCF effectively improve the visual function of NMDA-treated mice. Consistently, the activation of microglia in injured retina has also been inhibited after SCF treatment. Mechanistically, SCF administration not only prevent the loss of retinal ganglion cells (RGCs), but also maintained the function of RGCs as quantified by fERG. Further, we performed transcriptome sequencing analysis of the retinal cells isolated from SCF-treated mice and the parallel control. Gene Ontology analysis showed that SCF-induced transcriptome changes were closely correlated with eye development-related pathways. Crystallins and several protective factors such as Pitx3 were significantly upregulated by SCF treatment. Conclusions Our results revealed the role of c-Kit+ cells in the protection of RGCs in NMDA-treated mice, via inhibiting the loss of RGCs. Administration of SCF can act as a potent strategy for treating retinal degeneration-related diseases.

scholarly journals Cis-regulatory analysis of Onecut1 expression in fate-restricted retinal progenitor cells

2019 ◽  
Author(s):  
Sruti Patoori ◽  
Nathalie Jean-Charles ◽  
Ariana Gopal ◽  
Sacha Sulaiman ◽  
Sneha Gopal ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Large Scale ◽  
Statistical Tests ◽  
Regulatory Elements ◽  
Retinal Progenitor Cells ◽  
Retinal Progenitor ◽  
Reporter Assays ◽  
Gene Regulatory

BackgroundThe vertebrate retina consists of six major classes of neuronal cells. During development, these cells are generated from a pool of multipotent retinal progenitor cells (RPCs) that express the gene Vsx2. Fate-restricted RPCs have recently been identified, with limited mitotic potential and cell fate possibilities compared to multipotent RPCs. One population of fate-restricted RPCs, marked by activity of the regulatory element ThrbCRM1, gives rise to both cone photoreceptors and horizontal cells. These cells do not express Vsx2, but co-express the transcription factors (TFs) Onecut1 and Otx2, which bind to ThrbCRM1. The components of the gene regulatory networks that control the transition from multipotent to fate-restricted gene expression are not known. This work aims to identify and evaluate cis-regulatory elements proximal to Onecut1 to identify the gene regulatory networks involved in RPC fate-restriction.MethodWe identified regulatory elements through ATAC-seq and conservation, followed by reporter assays to screen for activity based on temporal and spatial criteria. The regulatory elements of interest were subject to deletion and mutation analysis to identify functional sequences and evaluated by quantitative flow cytometry assays. Finally, we combined the enhancer::reporter assays with candidate TF overexpression to evaluate the relationship between the TFs, the enhancers, and early vertebrate retinal development. Statistical tests included ANOVA, Kruskal-Wallis, or unpaired t-tests.ResultsTwo regulatory elements, ECR9 and ECR65, were identified to be active in ThrbCRM1(+) restricted RPCs. Candidate bHLH binding sites were identified as critical sequences in both elements. Overexpression of candidate bHLH TFs revealed specific enhancer-bHLH interactions. Nhlh1 overexpression expanded ECR65 activity into the Vsx2(+) RPC population, and overexpression of NeuroD1/NeuroG2/NeuroD4 had a similar effect on ECR9. Furthermore, bHLHs that were able to activate ectopic ECR9 reporter were able to induce endogenous Otx2 expression.ConclusionsThis work reports a large-scale screen to identify spatiotemporally specific regulatory elements near the Onecut1 locus. These elements were used to identify distinct populations in the developing retina. In addition, fate-restricted regulatory elements responded differentially to bHLH factors, and suggest a role for retinal bHLHs upstream of the Otx2 and Onecut1 genes during the formation of restricted RPCs from multipotent RPCs.

Different characteristics of rat retinal progenitor cells from different culture periods

2003 ◽  
Vol 341 (3) ◽  
pp. 213-216 ◽  
Author(s):  
Tadamichi Akagi ◽  
Masatoshi Haruta ◽  
Joe Akita ◽  
Akihiro Nishida ◽  
Yoshihito Honda ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Retinal Progenitor Cells ◽  
Retinal Progenitor ◽  
Different Characteristics
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