Transcriptional profiling of murine retinas undergoing semi-synchronous cone photoreceptor differentiation

Kaufman, Michael L.; Park, Ko Uoon; Goodson, Noah; Chew, Shereen; Bersie, Stephanie M.; Jones, Kenneth L.; Lamba, Deepak A.; Brzezinski, Joseph A.

doi:10.1016/j.ydbio.2019.05.016

Cited by 24 publications

(27 citation statements)

References 118 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…8 ). Our interpretation of these results is consistent with another recent developmental study that undertook a comprehensive transcriptome analysis of embryonic mouse retinas under conditions of Notch inhibition 42 . Here, it was reported that the earliest effects of Notch inhibition through DAPT treatment include the loss of multipotent RPC gene expression (observed as well by earlier studies of Notch1 and Rbpj), but also the early increase of genes that have identified primary correlations with restricted RPCs and with reduced to no expression in postmitotic cones 14 – 16 .…”

Section: Discussionsupporting

confidence: 91%

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

Chen

Emerson

2021

Sci Rep

View full text Add to dashboard Cite

Notch 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.

show abstract

Section: Discussionsupporting

confidence: 91%

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

Chen

Emerson

2021

Sci Rep

View full text Add to dashboard Cite

show abstract

“…The most prominent and consistent effects of Notch signaling we observed were on the formation of the ThrbCRM1-active restricted RPC population and a concomitant depletion of the multipotent RPC population, which suggests that the primary role for Notch signaling in cone formation is at the step of restricted RPC derivation from multipotent RPCs. Our interpretation of these results is consistent with another recent developmental study that undertook a comprehensive transcriptome analysis of DAPT-treated embryonic mouse retinas (Kaufman et al, 2019). Here, it was reported that the earliest effects of Notch inhibition through DAPT treatment include the loss of multipotent RPC gene expression (observed as well by earlier studies of Notch1 and Rbpj), but also the early increase of genes that have identified primary correlations with restricted RPCs and with reduced to no expression in postmitotic cones (Jadhav et al, 2006; Riesenberg et al, 2009; Yaron et al, 2006).…”

Section: Discussionsupporting

confidence: 92%

“…Many studies (Jadhav et al, 2006;Kaufman et al, 2019;Yaron et al, 2006) have identified a decrease in cycling cells when Notch signaling is inhibited.…”

Section: Discussionmentioning

confidence: 99%

“…All of these genes displayed a temporal dynamic consistent with increased production of restricted RPCs in this mouse model. In addition, several studies (Kaufman et al, 2019; Nelson et al, 2007) have identified an upregulation of several members of the bHLH family (NeuroD1, Ngn2, etc) which recent single cell analysis has associated with neurogenic RPCs and not multipotent RPCs (Lu et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…A role for Notch signaling in maintaining a self-renewing multipotent RPC population is also consistent with its observed effects on proliferation. Many studies (Jadhav et al, 2006b; Kaufman et al, 2019; Yaron et al, 2006) have identified a decrease in cycling cells when Notch signaling is inhibited. We did not detect a significant decrease within two days of electroporation, but consistent with other analysis at early time points in the mouse, there was only a partial loss of cycling cells.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

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

Chen

Emerson

2020

Preprint

View full text Add to dashboard Cite

Vertebrate 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.

show abstract

A framework to identify functional interactors that contribute to disrupted early retinal development in Vsx2 ocular retardation J mice

Leung

Rao

Raju

et al. 2023

Developmental Dynamics

View full text Add to dashboard Cite

BackgroundA goal of developmental genetics is to identify functional interactions that underlie phenotypes caused by mutations. We sought to identify functional interactors of Vsx2, which when mutated, disrupts early retinal development. We utilized the Vsx2 loss‐of‐function mouse, ocular retardation J (orJ), to assess interactions based on principles of positive and negative epistasis as applied to bulk transcriptome data. This was first tested in vivo with Mitf, a target of Vsx2 repression, and then to cultures of orJ retina treated with inhibitors of Retinoid‐X Receptors (RXR) to target Rxrg, an up‐regulated gene in the orJ retina, and gamma‐Secretase, an enzyme required for Notch signaling, a key mediator of retinal proliferation and neurogenesis.ResultsWhereas Mitf exhibited robust positive epistasis with Vsx2, it only partially accounts for the orJ phenotype, suggesting other functional interactors. RXR inhibition yielded minimal evidence for epistasis between Vsx2 and Rxrg. In contrast, gamma‐Secretase inhibition caused hundreds of Vsx2‐dependent genes associated with proliferation to deviate further from wild‐type, providing evidence for convergent negative epistasis with Vsx2 in regulating tissue growth.ConclusionsCombining in vivo and ex vivo testing with transcriptome analysis revealed quantitative and qualitative characteristics of functional interaction between Vsx2, Mitf, RXR, and gamma‐Secretase activities.

show abstract

Transcriptional profiling of murine retinas undergoing semi-synchronous cone photoreceptor differentiation

Cited by 24 publications

References 118 publications

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

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

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

A framework to identify functional interactors that contribute to disrupted early retinal development in Vsx2 ocular retardation J mice

Contact Info

Product

Resources

About