Compensation by tumor suppressor genes during retinal development in mice and humans

Donovan, Stacy L.; Schweers, Brett; Martins, Rodrigo A. P.; Johnson, Dianna A.; Dyer, Michael A.

doi:10.1186/1741-7007-4-14

Cited by 91 publications

(45 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It remains open how inactivation of Rb triggers HC death in various phases of the cell cycle, as we observed, and experiments focused on cell-cycle-or apoptosis-associated Rb pathway genes will be necessary. Although other pocket domain proteins (e.g., p130 and p107) can compensate for specific functions of Rb (28)(29)(30)(31)(32), the dramatic phenotype observed in our study can be simply explained by the reported absence of other pocket domain proteins in postnatal HCs (2).…”

Section: Chromatin Conformation In Rbmentioning

confidence: 69%

Rapid cell-cycle reentry and cell death after acute inactivation of the retinoblastoma gene product in postnatal cochlear hair cells

Weber

Corbett²,

Chow³

et al. 2008

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

View full text Add to dashboard Cite

Unlike lower vertebrates, mammals are unable to replace damaged mechanosensory hair cells (HCs) in the cochlea. Recently, ablation of the retinoblastoma protein (Rb) in undifferentiated mouse HC precursors was shown to cause cochlear HC proliferation and the generation of new HCs, raising the hope that inactivation of Rb in postmitotic HCs could trigger cell division and regenerate functional HCs postnatally. Here, we acutely inactivated Rb in nearly all cochlear HCs of newborn mice, using a newly developed HCspecific inducible Cre mouse line. Beginning 48 h after Rb deletion, Ϸ40% of HCs were in the S and M phases of the cell cycle, demonstrating an overriding role for Rb in maintaining the quiescent state of postnatal HCs. Unlike Rb-null HC precursors, such HCs failed to undergo cell division and died rapidly. HC clusters were restricted to the less differentiated cochlear regions, consistent with differentiation-dependent roles of Rb. Moreover, outer HCs expressed the maturation marker prestin, suggesting an embryonic time window for Rb-dependent HC specification. We conclude that Rb plays essential and age-dependent roles during HC proliferation and differentiation, and, in contrast to previous hypotheses, cell death after forced cell-cycle reentry presents a major challenge for mammalian HC regeneration from residual postnatal HCs. Genetic and environmental factors, such as noise and ototoxic drugs, can damage HCs, leading to their death and to permanent hearing loss. Mammalian HCs are not regenerated, whereas nonmammalian vertebrates are able to replenish lost sensory HCs by proliferation and differentiation of nearby SCs within the sensory epithelium (5-7). The critical difference in the regenerative ability of mammalian cochleae and nonmammalian hearing organs appears to be their proliferative responsiveness after trauma.A key inhibitor of proliferation is the retinoblastoma protein (Rb), a member of the family of pocket domain proteins. These proteins bind to E2F transcription factors and can repress genes required during the S phase, thereby maintaining cells in a quiescent state (reviewed in ref. 8). Rb is expressed in embryonic and postnatal HCs; its absence in HC precursors of mice led to the production of supernumerary HCs that appeared functional, demonstrating that mammalian HC precursors can indeed be manipulated to proliferate (9, 10). However, HC injury typically occurs after birth; our aim was therefore to determine whether the inactivation of Rb could trigger cell-cycle reentry in postnatal HCs. The consequences of Rb loss in vivo have been studied in many tissues, using mouse models (11); in this study, we inactivated Rb in postnatal HCs, using a newly developed tamoxifen-inducible Cre mouse line. We observed that HCs rapidly reentered the cell cycle after the loss of Rb but died without generating supernumerary HCs. Thus, forced cell-cycle reentry by Rb inactivation had an entirely different outcome in postnatal HCs than in embryonic precursor cells for HCs and SCs, having limited use for ...

show abstract

Section: Chromatin Conformation In Rbmentioning

confidence: 69%

Rapid cell-cycle reentry and cell death after acute inactivation of the retinoblastoma gene product in postnatal cochlear hair cells

Weber

Corbett²,

Chow³

et al. 2008

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

View full text Add to dashboard Cite

show abstract

“…A long-held belief in developmental neurobiology is that neurons cannot divide to produce more neurons once they have differentiated. While studying retinae from a series of mouse strains lacking different combinations of the Rb family of proteins (Rb, p107 and p130) [11, 53–55], mature horizontal neurons were discovered to re-enter the cell cycle and clonally divide while maintaining their differentiated features such as neurites and synaptic connections[54]. If left unchecked, the proliferating horizontal neurons formed aggressive, invasive retinoblastomas [54].…”

Section: Cellular Pliancy: a Unified Framework For Disease Susceptibimentioning

confidence: 99%

Lessons from Retinoblastoma: Implications for Cancer, Development, Evolution, and Regenerative Medicine

Dyer

2016

Trends in Molecular Medicine

View full text Add to dashboard Cite

Retinoblastoma is a rare childhood cancer of the developing retina, and studies on this orphan disease have led to fundamental discoveries in cancer biology. Retinoblastoma has also emerged as a model for translational research for pediatric solid tumors, which is particularly important as personalized medicine expands in oncology. Research on retinoblastomas has been combined with the exploration of retinal development and retinal degeneration to advance a new model of cell type–specific disease susceptibility termed ‘cellular pliancy’. The concept can even be extended to species-specific regeneration. This review discusses the remarkable path of retinoblastoma research and how it has shaped the most current efforts in basic, translational, and clinical research in oncology and beyond.

show abstract

“…Indeed, at least two cellular responses to Rb loss impede tumorigenesis in other settings, but evidently fail to do so in the cells from which retinoblastomas arise. First, in diverse settings including explanted mouse retinas, Rb loss is compensated by increased expression of the Rb-related p107 (Donovan et al, 2006). Second, loss of Rb can deregulate E2F transcription factors and elicit E2F-dependent apoptosis (Chen et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Retinoblastoma Has Properties of a Cone Precursor Tumor and Depends Upon Cone-Specific MDM2 Signaling

Fang

Lee

et al. 2009

Cell

205

286

View full text Add to dashboard Cite

SUMMARY Retinoblastomas develop due to the loss of the Rb protein, yet the cell type in which Rb suppresses retinoblastoma, and the cellular circuitry that underlies the need for Rb are undefined. Here, we show that retinoblastoma cells express markers of post-mitotic cone precursors, but not markers of other retinal cell types. We also demonstrate that human cone precursors prominently express MDM2 and N-Myc, that retinoblastoma cells require both of these proteins for proliferation and survival, and that MDM2 is specifically needed to suppress ARF-induced apoptosis in cultured retinoblastoma cells. Interestingly, retinoblastoma cell MDM2 expression was regulated by the cone-specific RXRγ transcription factor and a human-specific RXRγ consensus binding site, and proliferation required RXRγ as well as the cone-specific thyroid hormone receptor-β2. These findings provide support for a cone precursor origin of retinoblastoma and suggest that human cone-specific signaling circuitry sensitizes to the oncogenic effects of RB1 mutations.

show abstract

Compensation by tumor suppressor genes during retinal development in mice and humans

Cited by 91 publications

References 46 publications

Rapid cell-cycle reentry and cell death after acute inactivation of the retinoblastoma gene product in postnatal cochlear hair cells

Rapid cell-cycle reentry and cell death after acute inactivation of the retinoblastoma gene product in postnatal cochlear hair cells

Lessons from Retinoblastoma: Implications for Cancer, Development, Evolution, and Regenerative Medicine

Retinoblastoma Has Properties of a Cone Precursor Tumor and Depends Upon Cone-Specific MDM2 Signaling

Contact Info

Product

Resources

About