Persistent expression of cyclin D1 disrupts normal photoreceptor differentiation and retina development.
The differentiation 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 findings 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.
Skapek
S X
SX
Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. steve.skapek@stjude.org
Lin
S C
SC
Jablonski
M M
MM
McKeller
R N
RN
Tan
M
M
Hu
N
N
Lee
E Y
EY
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002455:Cell Division; D019938:Cyclin D1 / Q000096:biosynthesis* / Q000235:genetics; D016158:Genes, p53; D006965:Hyperplasia; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012160:Retina / Q000196:embryology* / Q000378:metabolism; D012175:Retinoblastoma / Q000378:metabolism; D019076:Transgenes
D019938:Cyclin D1