Abstract
Chicken horizontal progenitor cells are able to enter their final mitosis even in the presence of DNA damage despite having a functional p53-p21 system. This suggests that they are resistant to DNA damage and that the regulation of the final cell cycle of horizontal progenitor cells is independent of the p53-p21 system. The activity of p53 is regulated by positive and negative modulators, including the zinc finger containing transcription factor Zac1 (zinc finger protein that regulates apoptosis and cell cycle arrest). Zac1 interacts with and enhances the activity of p53, thereby inducing cell cycle arrest and apoptosis. In this work, we use a gain-of-function assay in which mouse Zac1 (mZac1) is overexpressed in chicken retinal progenitor cells to study the effect on the final cell cycle of horizontal progenitor cells. The results showed that overexpression of mZac1 induced expression of p21 in a p53-dependent way and arrested the cell cycle as well as triggered apoptosis in chicken non-horizontal retinal progenitor cells. The negative regulation of the cell cycle by mZac1 is consistent with its proposed role as a tumour-suppressor gene. However, the horizontal cells were not affected by mZac1 overexpression. They progressed into S- and late G2/M-phase despite overexpression of mZac1. The inability of mZac1 to arrest the cell cycle in horizontal progenitor cells support the notion that the horizontal cells are less sensitive to events that triggers the p53 system during their terminal and neurogenic cell cycle, compared with other retinal cells. These properties are associated with a cell that has a propensity to become neoplastic and thus with a cell that may develop retinoblastoma.
Highlights
Neurogenesis of the five neuronal cell types: retinal ganglion cells, photoreceptors (PRs), horizontal cells (HCs), amacrines, bipolars, and the Müller glia cell in the retina,[1] is coordinated by regulation of proliferation, cell cycle exit and differentiation of multipotent retinal progenitors
We were interested in the effects on the Lim homeobox protein 1 (Lim1)-expressing HCs because they exhibit an atypical regulation of their final cell cycle that seems not to be regulated by p53
Our previous results show that Lim1+ horizontal progenitor cell (HPC) are heterogenic with regards to when and during what cell cycle phase they leave the final cell cycle
Summary
Neurogenesis of the five neuronal cell types: retinal ganglion cells, photoreceptors (PRs), horizontal cells (HCs), amacrines, bipolars, and the Müller glia cell in the retina,[1] is coordinated by regulation of proliferation, cell cycle exit and differentiation of multipotent retinal progenitors. Once the cells undergo their final cell cycles, denoted as the terminal or neurogenic cell cycle, the cells withdraw from the cell cycle and initiate differentiation, while migrating to their final laminar position This is true for most of the retinal progenitor cells.[2,3] the final cell cycles of Lim homeobox protein 1 (Lim1) expressing HCs are different and some of the mitoses are performed as delayed non-apical mitoses.[4] Non-apical HC mitoses have been observed in zebrafish and chicken.[5,6] In chicken, these terminal mitoses take place on the basal side of the retina during a defined period of time,[4,5] and in combination with the specific expression of Lim[1] in HCs, it is possible to study the final cell cycle of these cells. The p21 mRNA expression levels were not significantly increased 48 h after electroporation compared with both non-treated or control-
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