Differentiated Horizontal Interneurons Clonally Expand to Form Metastatic Retinoblastoma in Mice

Ajioka, Itsuki; Martins, Rodrigo A. P.; Bayazitov, Ildar T.; Donovan, Stacy L.; Johnson, Dianna A.; Frase, Sharon; Cicero, Samantha A.; Boyd, Kelli L.; Zakharenko, Stanislav S.; Dyer, Michael A.

doi:10.1016/j.cell.2007.09.036

Cited by 173 publications

(186 citation statements)

References 29 publications

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“…This does not appear to be limited to chickens, as Godinho et al (21) recently used live imaging in the zebrafish retina to show the production of HCs by an INL progenitor making only HCs. Another recent study by Ajioka et al (22) reported that cells with differentiated HC features can divide in a murine model of retinoblastoma. This unusual property may be due to the fact that a mitotic cell committed to the HC fate is able to divide during normal development.…”

Section: Discussionmentioning

confidence: 98%

Retinal progenitor cells can produce restricted subsets of horizontal cells

Rompani

Cepko

2008

Proc. Natl. Acad. Sci. U.S.A.

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Section: Discussionmentioning

confidence: 98%

Retinal progenitor cells can produce restricted subsets of horizontal cells

Rompani

Cepko

2008

Proc. Natl. Acad. Sci. U.S.A.

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“…Other promising alternatives include the use of photoreceptor precursor cells from fetal retinae (18)(19)(20) or the use of ES cells (21,22). Of particular interest is the recent report that retinal neurons can be induced to reenter the cell cycle and make more retinal neurons without the need for stem cells or progenitor cells (23). If these studies can be extended to photoreceptors, then we might be able to generate new neurons in situ in a degenerating retina (23).…”

Section: Discussionmentioning

confidence: 99%

Cells previously identified as retinal stem cells are pigmented ciliary epithelial cells

Cicero

Johnson

Reyntjens³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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It was previously reported that the ciliary epithelium (CE) of the mammalian eye contains a rare population of cells that could produce clonogenic self-renewing pigmented spheres in culture. Based on their ability to up-regulate genes found in retinal neurons, it was concluded that these sphere-forming cells were retinal stem cells. This conclusion raised the possibility that CE-derived retinal stem cells could help to restore vision in the millions of people worldwide who suffer from blindness associated with retinal degeneration. We report here that human and mouse CE-derived spheres are made up of proliferating pigmented ciliary epithelial cells rather than retinal stem cells. All of the cells in the CE-derived spheres, including the proliferating cells, had molecular, cellular, and morphological features of differentiated pigmented CE cells. These differentiated cells ectopically expressed nestin when exposed to growth factors and low levels of pan-neuronal markers such as beta-III-tubulin. Although the cells aberrantly expressed neuronal markers, they retained their pigmented CE cell morphology and failed to differentiate into retinal neurons in vitro or in vivo. Our results provide an example of a differentiated cell type that can form clonogenic spheres in culture, self-renew, express progenitor cell markers, and initiate neuronal differentiation that is not a stem or progenitor cell. More importantly, our findings highlight the importance of shifting the focus away from studies on CE-derived spheres for cell-based therapies to restore vision in the degenerating retina and improving techniques for using ES cells or retinal precursor cells.O ver 40 million people worldwide are blind. Macular degeneration accounts for Ϸ8 million cases of blindness. Although the cause of macular degeneration is not known, 1 potential treatment is cell therapy. Stem cells hold great promise for regenerative medicine, and recently many efforts have been devoted to finding suitable candidates for retinal transplants. These candidates include photoreceptor progenitors (1) and embryonic stem cells (2, 3). Others have looked to the ciliary epithelium (CE) as a potential source of retinal stem cells (4, 5).In 2000, Tropepe and colleagues revealed that the CE of the mouse eye can be dissociated, maintained in culture at clonal density and stimulated to form clonogenic spheres (5). The CEderived spheres were pigmented, expressed nestin, and could be dissociated and replated to form spheres up to 8 times. When transferred to differentiation conditions in culture, cells from the CE-derived spheres up-regulated genes found in rod photoreceptors, bipolar neurons, and Müller glia (5). These findings were later extended to CE isolated from postmortem human eyes (4). Based on these and other data, it was suggested that the sphere-forming cells in the mammalian CE are retinal stem cells (RSCs) and, thus, hold promise for therapeutic replacement of retinal neurons lost to disease or degeneration.Given the potential impact of cell replacement ...

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“…Although not as tightly linked to tumor suppression as RB, tumor suppressive capacity has been assigned to these other family members in some contexts. In mouse studies, RB-deficient mice were prone to pituitary tumor formation (7), whereas mice deficient for RB and p107 or p130 developed retinoblastoma (8,9), suggesting that p107 and p130 can influence tissue specific predisposition toward tumor development. Similarly, conditional loss of p130 in adult lung epithelial cells in a RB Ϫ/Ϫ…”

mentioning

confidence: 99%

The Evolutionarily Conserved C-terminal Domains in the Mammalian Retinoblastoma Tumor Suppressor Family Serve as Dual Regulators of Protein Stability and Transcriptional Potency

Sengupta¹,

Lingnurkar²,

Carey³

et al. 2015

Journal of Biological Chemistry

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Background: RB family protein abundance is dynamic and sensitive to growth conditions. Results: RB family turnover is mediated by C-terminal degrons in a process that is phosphorylation-sensitive. Conclusion: The RB family degrons are important regulatory domains linking stability and transcriptional potency. Significance: Dual control of stability and potency by RB family degrons may contribute to embryonic development.

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Differentiated Horizontal Interneurons Clonally Expand to Form Metastatic Retinoblastoma in Mice

Cited by 173 publications

References 29 publications

Retinal progenitor cells can produce restricted subsets of horizontal cells

Retinal progenitor cells can produce restricted subsets of horizontal cells

Cells previously identified as retinal stem cells are pigmented ciliary epithelial cells

The Evolutionarily Conserved C-terminal Domains in the Mammalian Retinoblastoma Tumor Suppressor Family Serve as Dual Regulators of Protein Stability and Transcriptional Potency

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