Abstract
The cellular mechanisms controlling cell fate in self-renewal tissues remain unclear. Cell cycle failure often leads to an apoptosis anti-oncogenic response. We have inactivated Cdk1 or Polo-like-1 kinases, essential targets of the mitotic checkpoints, in the epithelia of skin and oral mucosa. Here, we show that inactivation of the mitotic kinases leading to polyploidy in vivo, produces a fully differentiated epithelium. Cells within the basal layer aberrantly differentiate and contain large or various nuclei. Freshly isolated KO cells were also differentiated and polyploid. However, sustained metaphase arrest downstream of the spindle anaphase checkpoint (SAC) due to abrogation of CDC20 (essential cofactor of anaphase-promoting complex), impaired squamous differentiation and resulted in apoptosis. Therefore, upon prolonged arrest keratinocytes need to slip beyond G2 or mitosis in order to initiate differentiation. The results altogether demonstrate that mitotic checkpoints drive squamous cell fate towards differentiation or apoptosis in response to genetic damage.
Highlights
The mechanisms coordinating proliferation, differentiation and apoptosis in self-renewal tissues are still intriguing.Edited by R.A
By directly causing mitotic stress at different levels we demonstrate the existence of a differentiation mitosis checkpoint (DMC) in squamous epithelia of the skin and oral mucosa
By comparing the epithelia in the absence of Cdk1, Plk1 or CDC20 we can begin to elucidate the molecular regulation of keratinocyte responses
Summary
The mechanisms coordinating proliferation, differentiation and apoptosis in self-renewal tissues are still intriguing. The control of cell fate upon DNA damage is important to homoeostasis and morphogenesis, even more in self-renewal tissues that are highly exposed to genotoxic agents. DNA damage caused by genotoxic agents (chemicals, UV irradiation) [6,7,8] or oncogenic replication stress, induces squamous differentiation This differentiation response is triggered via mitotic checkpoints and involves cytokinesis failure and endoreplication. Given the potential importance of the DMC to morphogenesis (homoeostasis and regeneration), we have investigated this issue in vivo To this end, we inactivated Cdk, Plk or CDC20 genes in mouse skin and oral epithelia. The results demonstrate that the G2/mitotic checkpoints control squamous differentiation They provide molecular mechanistic insight into the question why some cells differentiate while others undergo apoptosis in response to DNA damage. We discuss the strong implications into the control of self-renewal tissue homoeostasis and cancer
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