Heterogenic Final Cell Cycle by Chicken Retinal Lim1 Horizontal Progenitor Cells Leads to Heteroploid Cells with a Remaining Replicated Genome

Shahrzad Shirazi Fard,Miguel Jarrin,Valerie Fillon,Henrik Boije,Charlotta All-Eriksson,Finn Hallböök,Mike O Karl

doi:10.1371/journal.pone.0059133

Shahrzad Shirazi Fard, Miguel Jarrin + Show 5 more

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https://doi.org/10.1371/journal.pone.0059133

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Abstract

Retinal progenitor cells undergo apical mitoses during the process of interkinetic nuclear migration and newly generated post-mitotic neurons migrate to their prospective retinal layer. Whereas this is valid for most types of retinal neurons, chicken horizontal cells are generated by delayed non-apical mitoses from dedicated progenitors. The regulation of such final cell cycle is not well understood and we have studied how Lim1 expressing horizontal progenitor cells (HPCs) exit the cell cycle. We have used markers for S- and G2/M-phase in combination with markers for cell cycle regulators Rb1, cyclin B1, cdc25C and p27Kip1 to characterise the final cell cycle of HPCs. The results show that Lim1+ HPCs are heterogenic with regards to when and during what phase they leave the final cell cycle. Not all horizontal cells were generated by a non-apical (basal) mitosis; instead, the HPCs exhibited three different behaviours during the final cell cycle. Thirty-five percent of the Lim1+ horizontal cells was estimated to be generated by non-apical mitoses. The other horizontal cells were either generated by an interkinetic nuclear migration with an apical mitosis or by a cell cycle with an S-phase that was not followed by any mitosis. Such cells remain with replicated DNA and may be regarded as somatic heteroploids. The observed heterogeneity of the final cell cycle was also seen in the expression of Rb1, cyclin B1, cdc25C and p27Kip1. Phosphorylated Rb1-Ser608 was restricted to the Lim1+ cells that entered S-phase while cyclin B1 and cdc25C were exclusively expressed in HPCs having a basal mitosis. Only HPCs that leave the cell cycle after an apical mitosis expressed p27Kip1. We speculate that the cell cycle heterogeneity with formation of heteroploid cells may present a cellular context that contributes to the suggested propensity of these cells to generate cancer when the retinoblastoma gene is mutated.

Highlights

Cells of the central nervous system are formed during the process of interkinetic nuclear migration (INM) with S-phases on the basal side followed by apical mitoses [1,2,3]
Our results suggest that the final cell cycle of Lim1+ horizontal progenitor cells (HPCs) is heterogenic with regard to when the cells exit the cell cycle and we propose the existence of three behaviours
In this work we have studied the final cell cycle of Lim1+ HPCs in the chicken retina

Summary

Introduction

Cells of the central nervous system are formed during the process of interkinetic nuclear migration (INM) with S-phases on the basal side followed by apical mitoses [1,2,3]. The retina consists of neurons that undergo terminal mitosis on the apical side [9] and post-mitotic cells migrate to their prospective retinal layer This is valid for most of the five retinal neuronal classes but not for horizontal cells (HCs), which can be generated by non-apical mitoses. The expression of differentiation markers before the terminal mitosis resembles that of the cortical neurons, which initiates differentiation and migration before the neurogenic non-apical mitosis [6]. Another similarity between migrating HPCs and cortical progenitors is the expression of doublecortin [13,14]

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