Persistent expression of cyclin D1 disrupts normal photoreceptor differentiation and retina development

Abstract

The dierentiation of neuronal cells in the developing mammalian retina is closely coupled to cell cycle arrest and proceeds in a highly organized manner. Cyclin D1, which regulates cell proliferation in many cells, also drives the proliferation of photoreceptor progenitors. In the mouse retina, cyclin D1 protein normally decreases as photoreceptors mature. To study the importance of the down-regulation of cyclin D1 during photoreceptor development, we generated a transgenic mouse in which cyclin D1 was persistently expressed in developing photoreceptor cells. We observed numerous abnormalities in both photoreceptors and other nonphotoreceptor cells in the retina of these transgenic mice. In particular, we observed delayed opsin expression in developing photoreceptors and alterations in their number and morphology in the mature retina. These alterations were accompanied by disorganization of the inner nuclear and plexiform layers. The expression of cyclin D1 caused excess photoreceptor cell proliferation and apoptosis. Loss of the p53 tumor suppressor gene decreased cyclin D1-induced apoptosis and led to microscopic hyperplasia in the retina. These ®ndings are distinct from other mouse models in which the retinoblastoma gene pathway is disrupted and suggest that the IRBP ± cyclin D1 mouse model may recapitulate an early step in the development of retinoblastoma. Oncogene (2001) 20, 6742 ± 6751.

Evidence for an evolutionary conserved role ofhomothorax/Meis1/2during vertebrate retina development

“…Meis2 overexpression failed to induce cyclin D1 expression (data not shown; n=12). Our finding that Meis function is important for RPC proliferation and cyclin D1 expression, together with earlier studies that have associated cyclin D1 levels with the modulation of cell cycle kinetics in the retina, suggest that Meis proteins play a role in the regulation of retinal progenitor cell number through influencing the expression of cell cycle components (Green et al, 2003;Locker et al, 2006;Skapek et al, 2001;Wang et al, 2005;Yamaguchi et al, 2005). Similar observations have been made independently by Bessa et al (Bessa et al, 2008).…”

Regulation of cell lineage specification by the retinoblastoma tumor suppressor

“…This appears to be a cell-autonomous effect because defective rod development is also observed in individual cells where RB is targeted by retroviralmediated Cre expression (Zhang et al, 2004a). Loss of photoreceptor differentiation in this model is consistent with a previous study where RB family proteins were functionally inactivated due to transgenic expression of Cyclin D1 under control of the Interphotoreceptor retinoid-binding protein promoter (Skapek et al, 2001). In all these cases, excess proliferation that occurs in the maturing retina without RB is balanced by apoptosis, which likely results in decreased numbers of photoreceptors (Chen et al, 2004;MacPherson et al, 2004;Zhang et al, 2004a).…”

Retinal horizontal cells: challenging paradigms of neural development and cancer biology

“…These data directly challenge the widely held belief in the field of developmental biology that passage through the cell cycle is incompatible with a fully differentiated status (Skapek et al, 2001;Yang et al, 2001). The above-mentioned study was aimed at clarifying the complex functional redundancy that is exhibited by Rb family members during retinal development and tumorigenesis (Chen et al, 2004;Donovan et al, 2006;MacPherson et al, 2004;Zhang et al, 2004 (hereafter 'p107-single') mice, which have a single functional copy of p107, were thoroughly characterized (Ajioka et al, 2007).…”