Cyclin D1 fine-tunes the neurogenic output of embryonic retinal progenitor cells.
BACKGROUND
Maintaining the correct balance of proliferation versus differentiation in retinal progenitor cells (RPCs) is essential for proper development of the retina. The cell cycle regulator cyclin D1 is expressed in RPCs, and mice with a targeted null allele at the cyclin D1 locus (Ccnd1-/-) have microphthalmia and hypocellular retinas, the latter phenotype attributed to reduced RPC proliferation and increased photoreceptor cell death during the postnatal period. How cyclin D1 influences RPC behavior, especially during the embryonic period, is unclear.


RESULTS
In this study, we show that embryonic RPCs lacking cyclin D1 progress through the cell cycle at a slower rate and exit the cell cycle at a faster rate. Consistent with enhanced cell cycle exit, the relative proportions of cell types born in the embryonic period, such as retinal ganglion cells and photoreceptor cells, are increased. Unexpectedly, cyclin D1 deficiency decreases the proportions of other early born retinal neurons, namely horizontal cells and specific amacrine cell types. We also found that the laminar positioning of horizontal cells and other cell types is altered in the absence of cyclin D1. Genetically replacing cyclin D1 with cyclin D2 is not efficient at correcting the phenotypes due to the cyclin D1 deficiency, which suggests the D-cyclins are not fully redundant. Replacement with cyclin E or inactivation of cyclin-dependent kinase inhibitor p27Kip1 restores the balance of RPCs and retinal cell types to more normal distributions, which suggests that regulation of the retinoblastoma pathway is an important function for cyclin D1 during embryonic retinal development.


CONCLUSIONS
Our findings show that cyclin D1 has important roles in RPC cell cycle regulation and retinal histogenesis. The reduction in the RPC population due to a longer cell cycle time and to an enhanced rate of cell cycle exit are likely to be the primary factors driving retinal hypocellularity and altered output of precursor populations in the embryonic Ccnd1-/- retina.
Department of Ophthalmology and Visual Sciences, John A Moran Eye Center, University of Utah, Salt Lake City, UT 84132, USA. gaurav.das@hsc.utah.edu
Gaurav
G
Das
Yoon
Y
Choi
Piotr
P
Sicinski
Edward M
EM
Levine
D000818:Animals; D000831:Animals, Newborn; D001973:Bromodeoxyuridine / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D019938:Cyclin D1 / Q000172:deficiency / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000172:deficiency; D004622:Embryo, Mammalian; D053595:Embryonic Stem Cells / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D051857:Otx Transcription Factors / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012160:Retina / Q000166:cytology* / Q000196:embryology* / Q000254:growth & development; D013936:Thymidine / Q000378:metabolism; D050820:Transcription Factor Brn-3B / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism
C530105:Ccnd1 protein, mouse; C493961:Cdkn1b protein, mouse; D018398:Homeodomain Proteins; D051857:Otx Transcription Factors; C497660:Otx2 protein, mouse; C085559:Pou4f2 protein, mouse; D018809:Proliferating Cell Nuclear Antigen; D050820:Transcription Factor Brn-3B; D014404:Tubulin; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D001973:Bromodeoxyuridine; D013936:Thymidine