NONLETHAL ULTRAVIOLET LIGHT (UV) INDUCES SQUAMOUS DIFFERENTIATION

NEW WORK IN CELL DEATH AND DISEASE -OPEN ACCESS

The skin might maintain homeostasis in spite to daily exposure to UV light thanks to this mechanism.


Cell Death & Disease  volume 9, Article number: 1094 (2018)
https://www.nature.com/articles/s41419-018-1130-8

Sublethal UV irradiation induces squamous differentiation via a p53-independent, DNA damage-mitosis checkpoint

de Pedro I, Alonso-Lecue P, Sanz-Gómez N, Freije A, Gandarillas A
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.

On the press

NEW WORK ON RARE DISEASE IN SCIENTIFIC REPORTS -OPEN ACCESS

Primary cell cultures have an enormous mostly unexplored potential on rare diseases. Having the possibility to amplify and store cells from the patient allows genetic and cell behavioural studies. This allows not only identification of the associated mutation, leading to diagnosis, but also investigating the molecular and cellular mechanisms underlying the disease. Our work just out in Scientific Reports is an illustration of this potential.

https://www.nature.com/articles/s41598-018-36859-2

Cellular and animal models of skin alterations in the autism-related ADNP syndrome

Mollinedo P^1,2, Kapitansky O³, Gonzalez-Lamuño D^4,2, Zaslavsky A³, Real P⁵, Gozes I³, Gandarillas A⁶, Fernandez-Luna JL^7,8

Scientific Reportsvolume 9, Article number: 736 (2019) | Download Citation

 

Abstract

Mutations in ADNP have been recently associated with intellectual disability and autism spectrum disorder. However, the clinical features of patients with this syndrome are not fully identified, and no treatment currently exists for these patients. Here, we extended the ADNP syndrome phenotype describing skin abnormalities in both a patient with ADNP syndrome and an Adnp haploinsufficient mice. The patient displayed thin dermis, hyperkeratotic lesions in periarticular areas and delayed wound healing. Patient-derived skin keratinocytes showed reduced proliferation and increased differentiation. Additionally, detection of cell cycle markers indicated that mutant cells exhibited impaired cell cycle progression. Treatment of ADNP-deficient keratinocytes with the ADNP-derived NAP peptide significantly reduced the expression of differentiation markers. Sonography and immunofluorescence staining of epidermal layers revealed that the dermis was thinner in the patient than in a healthy control. Adnp haploinsufficient mice (Adnp^+/−) mimicked the human condition showing reduced dermal thickness. Intranasal administration of NAP significantly increased dermal thickness and normalized the levels of cell cycle and differentiation markers. Our observations provide a novel activity of the autism-linked ADNP in the skin that may serve to define the clinical phenotype of patients with ADNP syndrome and provide an attractive therapeutic option for skin alterations in these patients.