Abstract
BackgroundNeuropilin 1 (NRP1) is expressed on several cell types including neurons and endothelial cells, where it functions as an important regulator in development and during angiogenesis. As a cell surface receptor, NRP1 is able to bind to members of the VEGF family of growth factors and to secreted class 3 semaphorins. Neuropilin 1 is also highly expressed in keratinocytes, but the function of NRP1 in epidermal physiology and pathology is still unclear.Methods and ResultsTo elucidate the role of NRP1 in skin in vivo we generated an epidermis-specific neuropilin 1 knock out mouse model by using the Cre-LoxP-System. Mice were viable and fertile and did not display any obvious skin or hair defects. After challenge with UVB irradiation, we found that deletion of epidermal NRP1 leads to increased rates of apoptosis both in vitro and in vivo. NRP1-deficient primary keratinocytes cultured in vitro showed significantly higher rates of apoptosis 24 hours after UVB. Likewise, there is a significant increase of active caspase 3 positive cells in the epidermis of Keratin 14-Cre-NRP1 (−/−) mice 24 hours after UVB irradiation. By Western Blot analysis we could show that NRP1 influences the cytosolic levels of Bcl-2, a pro-survival member of the Bcl-2 family. After UVB irradiation the amounts of Bcl-2 decrease in both protein extracts from murine epidermis and in NRP1-deficient keratinocytes in vitro, whereas wild type cells retain their Bcl-2 levels. Likewise, levels of phospho-Erk and Rac1 were lower in NRP1-knock out keratinocytes, whereas levels of pro-apoptotic p53 were higher.ConclusionNRP1 expression in keratinocytes is dispensable for normal skin development. Upon UVB challenge, NRP1 contributes to the prevention of keratinocyte apoptosis. This pro-survival function of NRP1 is accompanied by the maintenance of high levels of the antiapoptotic regulator Bcl-2 and by lower levels of pro-apoptotic p53.
Highlights
Like no other organ the human skin as the outer protective barrier of the body is exposed to a variety of external insults
Neuropilin 1 (NRP1) expression in keratinocytes is dispensable for normal skin development
Upon UVB challenge, NRP1 contributes to the prevention of keratinocyte apoptosis
Summary
Like no other organ the human skin as the outer protective barrier of the body is exposed to a variety of external insults. The epidermis, consisting mainly of keratinocytes forming a stratified epithelium, is continuously exposed to environmental hazards This challenge by carcinogens is reflected by the fact that epithelial skin cancer is the most common neoplastic disease in humans [1]. The main components for programmed cell death are permanently present in epidermal keratinocytes and need to be suppressed during early phases of differentiation in the basal and suprabasal layers. This prevention of premature cell death depends on the permanent stimulation with mitogens like EGF, KGF or HGF. Neuropilin 1 is highly expressed in keratinocytes, but the function of NRP1 in epidermal physiology and pathology is still unclear
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