Among the most intriguing and relevant questions in physiology is how developing tissues correctly coordinate proliferation with differentiation. Endoreplication, in a broad sense, is a consequence of a cell division block in the presence of an active cell cycle, and it typically occurs as cells differentiate terminally to fulfill a specialised function. Until recently, endoreplication was thought to be a rare variation of the cell cycle in mammals, more common in invertebrates and plants. However, in the last years, endoreplication has been uncovered in various tissues in mammalian organisms, including human. A recent report showing that cells in the mammary gland become binucleate at lactation sheds new insight into the importance of mammalian polyploidisation. We here propose that endoreplication is a widespread phenomenon in mammalian developing tissues that results from an automatic, robust and simple self-limiting mechanism coordinating cell multiplication with differentiation. This mechanism might act as a developmental timer. The model has implications for homeostasis control and carcinogenesis.

The epidermis is a self-renewal epithelium continuously exposed to the genotoxic effects of ultraviolet (UV) light, the main cause of skin cancer. Therefore, it needs robust self-protective mechanisms facing genomic damage. p53 has been shown to mediate apoptosis in sunburn cells of the epidermis. However, epidermal cells daily receive sublethal mutagenic doses of UV and massive apoptosis would be deleterious. We have recently unravelled an anti-oncogenic keratinocyte DNA damage-differentiation response to cell cycle stress. We now have studied this response to high or moderate single doses of UV irradiation. Whereas, as expected, high levels of UV induced p53-dependent apoptosis, moderate levels triggered squamous differentiation. UV-induced differentiation was not mediated by endogenous p53. Overexpression of the mitosis global regulator FOXM1 alleviated the proliferative loss caused by UV. Conversely, knocking-down the mitotic checkpoint protein Wee1 drove UV-induced differentiation into apoptosis. Therefore, the results indicate that mitosis checkpoints determine the response to UV irradiation. The differentiation response was also found in cells of head and neck epithelia thus uncovering a common regulation in squamous tissues upon chronic exposure to mutagens, with implications into homeostasis and disease.

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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.

Background Squamous epithelia of the head and neck undergo continuous cell renewal and are continuously exposed to mutagenic hazard, the main cause of cancer. How they maintain homeostasis upon cell cycle deregulation is unclear. Methods To elucidate how head and neck epithelia respond to cell cycle stress, we studied human keratinocytes from various locations (oral mucosa, tonsil, pharynx, larynx, and trachea). We made use of genotoxic or mitotic drugs (doxorubicin [DOXO], paclitaxel, and nocodazole), or chemical inhibitors of the mitotic checkpoint kinases, Aurora B and polo‐like‐1. We further tested the response to inactivation of p53, ectopic cyclin E, or to the chemical carcinogen 7,12‐dimethylbenz[a]anthracene (DMBA). Results All treatments provoked DNA damage or mitosis impairment and strikingly triggered squamous differentiation and polyploidization, resulting in irreversible loss of clonogenic capacity. Conclusion Keratinocytes from head and neck epithelia share a cell‐autonomous squamous DNA damage‐differentiation response that is common to the epidermis and might continuously protect them from cancer.