Cell cycle perturbation uncouples mitotic progression and invasive behavior in a post-mitotic cell

Abstract

The acquisition of the post-mitotic state is crucial for the execution of many terminally differentiated cell behaviors during organismal development. However, the mechanisms that maintain the post-mitotic state in this context remain poorly understood. To gain insight into these mechanisms, we used the genetically and visually accessible model of C. elegans anchor cell (AC) invasion into the vulval epithelium. The AC is a terminally differentiated uterine cell that must exit the cell cycle and enter a post-mitotic to initiate contact between the uterus and vulva through a cell invasion event. Here, we set out to identify the negative cell cycle regulators that maintain the AC in a post-mitotic, invasive state. Although our findings revealed a critical role for CKI-1 (p21CIP1/p27KIP1) in maintaining the post-mitotic state of the AC, loss of CKI-1 alone or in combination with other negative cell cycle regulators-including CKI-2 (p21CIP1/p27KIP1), LIN-35 (pRb/p107/p130), FZR-1 (Cdh1/Hct1), and LIN-23 (Beta-TrCP) resulted in proliferating ACs that retained their invasive abilities. Upon examination of the gene regulatory network controlling AC invasion, we determined that proliferating, invasive ACs maintain pro-invasive gene expression. We therefore report that maintenance of the post-mitotic state is not necessary for AC invasion, breaking the previously established C. elegans invasion/proliferation dichotomy.

The proliferation and differentiation programs are only partially coupled duringC. elegansintestine development

“…Although this is indeed the case in some instances (e.g. (Willms et al, 2020)), the situation appears to be more complex than anticipated and some examples of uncoupling between cell cycle exit and differentiation have been described (Cockburn et al, 2022;Lobjois et al, 2008;Martinez et al, 2024). We therefore decided to investigate further how changes in cell proliferation affect differentiation during development and, reciprocally, how differentiation contributes to cell cycle regulation.…”