title: The terminal basal mitosis of chicken retinal Lim1 horizontal cells is not sensitive to cisplatin-induced cell cycle arrest.
abstract: For proper development, cells need to coordinate proliferation and cell cycle-exit. This is mediated by a cascade of proteins making sure that each phase of the cell cycle is controlled before the initiation of the next. Retinal progenitor cells divide during the process of interkinetic nuclear migration, where they undergo S-phase on the basal side, followed by mitoses on the apical side of the neuroepithelium. The final cell cycle of chicken retinal horizontal cells (HCs) is an exception to this general cell cycle behavior. Lim1 expressing (+) horizontal progenitor cells (HPCs) have a heterogenic final cell cycle, with some cells undergoing a terminal mitosis on the basal side of the retina. The results in this study show that this terminal basal mitosis of Lim1+ HPCs is not dependent on Chk1/2 for its regulation compared to retinal cells undergoing interkinetic nuclear migration. Neither activating nor blocking Chk1 had an effect on the basal mitosis of Lim1+ HPCs. Furthermore, the Lim1+ HPCs were not sensitive to cisplatin-induced DNA damage and were able to continue into mitosis in the presence of γ-H2AX without activation of caspase-3. However, Nutlin3a-induced expression of p21 did reduce the mitoses, suggesting the presence of a functional p53/p21 response in HPCs. In contrast, the apical mitoses were blocked upon activation of either Chk1/2 or p21, indicating the importance of these proteins during the process of interkinetic nuclear migration. Inhibiting Cdk1 blocked M-phase transition both for apical and basal mitoses. This confirmed that the cyclin B1-Cdk1 complex was active and functional during the basal mitosis of Lim1+ HPCs. The regulation of the final cell cycle of Lim1+ HPCs is of particular interest since it has been shown that the HCs are able to sustain persistent DNA damage, remain in the cell cycle for an extended period of time and, consequently, survive for months.
authors.affiliation: a Department of Neuroscience ; BMC Uppsala University ; Uppsala , Sweden.
authors.forename: Shahrzad
authors.initials: S
authors.lastname: Shirazi Fard
authors.forename: Malin
authors.initials: M
authors.lastname: Thyselius
authors.forename: Charlotta
authors.initials: C
authors.lastname: All-Ericsson
authors.forename: Finn
authors.initials: F
authors.lastname: Hallböök
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000502:physiology*; D002645:Chickens; D002945:Cisplatin / Q000633:toxicity*; D060850:LIM-Homeodomain Proteins / Q000096:biosynthesis*; D008938:Mitosis / Q000187:drug effects / Q000502:physiology*; D051248:Retinal Horizontal Cells / Q000187:drug effects / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis*
chemical_list: D000970:Antineoplastic Agents; C085473:LHX1 protein, human; D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors; D002945:Cisplatin
keywords: ATM, ataxia telangiectasia mutated; ATM/ATR; ATR, ataxia telangiectasia Rad-3 related protein; C-casp-3, cleaved caspase 3; Cdk1, cyclin-dependent kinase 1; Chk1, checkpoint kinase 1; Chk2, checkpoint kinase 2; E, Embryonic day;; HCs, horizontal cells; HPCs, horizontal progenitor cells; INM, interkinetic nuclear migration; Mdm2, murine double minute 2; Mdm4/X, murine double minute 4/X; Nutlin3a; PH3, PhosphoHistone 3; TBP, TATA binding protein; cell cycle regulation; chk1; cyclin B1-Cdk1; p21; p21, p21CIP1/waf1;; p53; retina; st, stage; γ-H2AX, phosphorylated histone H2AX