Loss of cell cycle control renders cells nonresponsive to local extrinsic differentiation cues

Abstract

5 control, zebrafish, hdac1, cyclin dependent kinase inhibitors 6 7 Abstract 23 Objective and approaches: Aberrantly proliferating cells are linked to a number of diseases 24 including cancers and developmental defects.To determine the extent to which local extrinsic 25 signals contribute to or ameliorate mutant cell behaviors, we examined survival and differentiation 26 of mutant cells in wild-type retinal environments by generating chimeric zebrafish embryos 27 comprised of unlabeled host cells and GFP-labeled neural progenitor donor cells. In addition, we 28 examined the fate of retinal progenitor cells when cdkn1c, a cyclin dependent kinase inhibitor, 29 was induced in clones within wild-type and hdac1 mutant retinae. 30Results: We found that seven of the ten mutants examined exhibited apoptosis when grafted into 31 wild-type tissue, with cells from two slowly cycling mutants, elys and emi1, noticeably 32 differentiating in a wild-type environment. Observations of the one hyperproliferative mutant, 33 hdac1, revealed that these mutant cells did not appear to die or differentiate but instead survived 34 and formed tumor-like rosettes in a wild-type environment. Ectopic expression of cdkn1c was 35 unable to force cell cycle exit and differentiation of the majority of hdac1 mutant cells. 36Conclusions: Together, these results suggest that although a wild-type environment rarely 37 encourages cell cycle exit and differentiation of neural progenitors with cell cycle defects, wild-38 type survival signals may enable hyperproliferative progenitor cells to persist instead of die.