Reconciling competence and transcriptional hierarchies with stochasticity in retinal lineages

Boije, Henrik; Macdonald, R.; Harris, William A.

doi:10.1016/j.conb.2014.02.014

Cited by 46 publications

(55 citation statements)

References 54 publications

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“…Next, we tested the expression of key retinal developmental genes, specific to particular cell types. Atoh7, Islet1, and Onecut2 are expressed early in retinal neurogenesis and are important for generation of retinal ganglion cells and other early‐generated cell types, whereas Otx2 is necessary for photoreceptors and bipolar cells (Boije et al, ). Ascl1 transduction resulted in a significant upregulation of all of these genes, in accordance to our previous study (Pollak et al, ).…”

Section: Resultsmentioning

confidence: 99%

miR‐124‐9‐9* potentiates Ascl1‐induced reprogramming of cultured Müller glia

Wohl

Reh

2016

Glia

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The Müller glia of fish provide a source for neuronal regeneration after injury, but they do not do so in mammals. We previously showed that lentiviral gene transfer of the transcription factor Achaete-scute homolog 1 (Ascl1/Mash1) in murine Müller glia cultures resulted in partial reprogramming of the cells to retinal progenitors. The microRNAs (miRNAs) miR-124-9-9* facilitate neuronal reprogramming of fibroblasts, but their role in glia reprogramming has not been reported. The aim of this study was to test whether 1) lentiviral gene transfer of miR-124-9-9* can reprogram Müller glia into retinal neurons and 2) miR-124-9-9* can improve Ascl1-induced reprogramming. Primary Müller glia cultures were generated from postnatal day (P) 11/12 mice, transduced with lentiviral particles, i.e., miR-124-9-9*-RFP, nonsense-RFP, Ascl1-GFP or GFP-control. Gene expression and immunofluorescence analyses were performed within 3 weeks after infection. Overexpression of miR-124-9-9* induced the expression of the proneural factor Ascl1 and additional markers of neurons, including TUJ1 and MAP2.When Ascl1 and miR-124-9-9* were combined, 50-60% of Müller glia underwent neuronal reprogramming, whereas Ascl1 alone results in a 30-35% reprogramming rate.Analysis of the miR-124-9-9* treated glial cells showed a reduction in the level of Ctdsp1 and Ptbp1, indicating a critical role for the REST pathway in the repression of neuronal genes in Müller glia.Our data further suggest that miR-124-9-9* and the REST complex may play a role in regulating the reprogramming of Müller glia to progenitors that underlies retinal regeneration in zebrafish.

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Section: Resultsmentioning

confidence: 99%

miR‐124‐9‐9* potentiates Ascl1‐induced reprogramming of cultured Müller glia

Wohl

Reh

2016

Glia

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“…Furthermore ATOH7 expressing progenitors do not exclusively develop into RGCs, as lineage tracing of ATOH7+ cells revealed that many ATOH7+ cells become amacrine cells, horizontal cells, and rod and cone photoreceptors (Brzezinski et al, 2012; Feng et al, 2010). Thus, it will be interesting in future studies to understand the nature of all the cells in the CD184hi population especially given the heterogeneous character of RPCs and probabilistic decisions associated with RPC cell fate commitment (Boije et al, 2014; Cepko, 2014; Kiyama et al, 2011; Trimarchi et al, 2008). The CD184hi CD171+ fraction showed variable enrichment of transcripts for inner neurons ( TFAB2B, PTF1A, LIM1, PROX1 ) and photoreceptors ( CRX ) suggesting that photoreceptors, horizontal and amacrine cells can be present (Figures 5G and S5).…”

Section: Discussionmentioning

confidence: 99%

Temporal expression of CD184(CXCR4) and CD171(L1CAM) identifies distinct early developmental stages of human retinal ganglion cells in embryonic stem cell derived retina

Aparicio

Hopp

Choi

et al. 2017

Experimental Eye Research

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Human retinal ganglion cells (RGCs) derived from pluripotent stem cells (PSCs) have anticipated value for human disease study, drug screening, and therapeutic applications; however, their full potential remains underdeveloped. To characterize RGCs in human embryonic stem cell (hESC) derived retinal organoids we examined RGC markers and surface antigen expression and made comparisons to human fetal retina. RGCs in both tissues exhibited CD184 and CD171 expression and distinct expression patterns of the RGC markers BRN3 and RBPMS. The retinal progenitor cells (RPCs) of retinal organoids expressed CD184, consistent with its expression in the neuroblastic layer in fetal retina. In retinal organoids CD184 expression was enhanced in RGC competent RPCs and high CD184 expression was retained on post-mitotic RGC precursors; CD171 was detected on maturing RGCs. The differential expression timing of CD184 and CD171 permits identification and enrichment of RGCs from retinal organoids at differing maturation states from committed progenitors to differentiating neurons. These observations will facilitate molecular characterization of PSC-derived RGCs during differentiation, critical knowledge for establishing the veracity of these in vitro produced cells. Furthermore, observations made in the retinal organoid model closely parallel those in human fetal retina further validating use of retinal organoid to model early retinal development.

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“…In a recent review, Boije et al () emphasize stochasticity, in the sense that all fates are available to all cells at any one time. We stress, however, that even though each individual cell might stochastically differentiate into one of the limited fates available, there are strong signs of tight regulation of the differentiation process, with most cell sub‐types involved in the control of their temporal restriction.…”

Section: Similarities and Differences Between Homeostatic And Developmentioning

confidence: 99%

Cell dynamics and gene expression control in tissue homeostasis and development

Rué

Arias

2015

Molecular Systems Biology

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During tissue and organ development and maintenance, the dynamic regulation of cellular proliferation and differentiation allows cells to build highly elaborate structures. The development of the vertebrate retina or the maintenance of adult intestinal crypts, for instance, involves the arrangement of newly created cells with different phenotypes, the proportions of which need to be tightly controlled. While some of the basic principles underlying these processes developing and maintaining these organs are known, much remains to be learnt from how cells encode the necessary information and use it to attain those complex but reproducible arrangements. Here, we review the current knowledge on the principles underlying cell population dynamics during tissue development and homeostasis. In particular, we discuss how stochastic fate assignment, cell division, feedback control and cellular transition states interact during organ and tissue development and maintenance in multicellular organisms. We propose a framework, involving the existence of a transition state in which cells are more susceptible to signals that can affect their gene expression state and influence their cell fate decisions. This framework, which also applies to systems much more amenable to quantitative analysis like differentiating embryonic stem cells, links gene expression programmes with cell population dynamics.

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Reconciling competence and transcriptional hierarchies with stochasticity in retinal lineages

Cited by 46 publications

References 54 publications

miR‐124‐9‐9* potentiates Ascl1‐induced reprogramming of cultured Müller glia

miR‐124‐9‐9* potentiates Ascl1‐induced reprogramming of cultured Müller glia

Temporal expression of CD184(CXCR4) and CD171(L1CAM) identifies distinct early developmental stages of human retinal ganglion cells in embryonic stem cell derived retina

Cell dynamics and gene expression control in tissue homeostasis and development

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