The cyclin-dependent kinase inhibitors p19(Ink4d) and p27(Kip1) are coexpressed in select retinal cells and act cooperatively to control cell cycle exit.
Cyclin-dependent kinase inhibitors (cdki's), including p19(Ink4d) and p27(Kip1), mediate exit from the cell cycle. To determine the function of these cdki's in regulating neurogenesis, we examined retina from wild-type, Ink4d-null, and Ink4d/Kip1-double null animals. Ink4d was expressed in progenitors and select neurons in the mature retina. Ink4d-null retina showed an extended period of proliferation, followed by apoptosis. Colabeling for p19(Ink4d) and p27(Kip1) revealed that a subpopulation of cells expressed both inhibitors. Deletion of Ink4d and Kip1 resulted in continued proliferation that was synergistic. This hyperproliferation led to an increase in number of horizontal cells and differentiated neurons reentering the cell cycle. Deletion of Ink4d and Kip1 also exacerbated the retinal dysplasia observed in Kip1-null mice, which was shown to be partly dependent on p53. These data indicate that select retinal cells express both p19(Ink4d) and p27(Kip1) and that they act cooperatively to ensure cell cycle exit.
Cunningham
Justine J
JJ
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, Tennessee 38105, USA.
Levine
Edward M
EM
Zindy
Frederique
F
Goloubeva
Olga
O
Roussel
Martine F
MF
Smeyne
Richard J
RJ
D025042:Amacrine Cells / Q000166:cytology* / Q000502:physiology; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D016923:Cell Death / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D050764:Cyclin-Dependent Kinase Inhibitor p19; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D018816:Genes, cdc / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015792:Retinal Dysplasia / Q000235:genetics / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000166:cytology* / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics*
C493961:Cdkn1b protein, mouse; C493975:Cdkn2d protein, mouse; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050764:Cyclin-Dependent Kinase Inhibitor p19; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27