Keratinocytes from APP/APLP2-deficient mice are impaired in proliferation, adhesion and migration in vitro

• Published in: Experimental cell research 2006-07, Vol.312 (11), p.1939-1949
• Main Authors: Siemes, Christina, Quast, Thomas, Kummer, Christiane, Wehner, Sven, Kirfel, Gregor, Müller, Ulrike, Herzog, Volker
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - pharmacology; Amyloid beta-Protein Precursor - physiology; Animals; Cell Adhesion; Cell adhesion & migration; Cell Movement; CELL PROLIFERATION; Cell Proliferation - drug effects; Cells, Cultured; EPIDERMIS; FIBROBLASTS; Gene expression; GROWTH FACTORS; IN VITRO; IN VIVO; Keratinocytes - cytology; Keratinocytes - drug effects; Keratinocytes - physiology; KNOCK-OUT REACTIONS; MICE; Mice, Knockout; Microscopy, Video; Proteins; Recombinant Proteins - genetics; Rodents
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2006.02.025

Growing evidence shows that the soluble N-terminal form (sAPPα) of the amyloid precursor protein (APP) represents an epidermal growth factor fostering keratinocyte proliferation, migration and adhesion. APP is a member of a protein family including the two mammalian amyloid precursor-like proteins APLP1 and APLP2. In the mammalian epidermis, only APP and APLP2 are expressed. APP and APLP2-deficient mice die shortly after birth but do not display a specific epidermal phenotype. In this report, we investigated the epidermis of APP and/or APLP2 knockout mice. Basal keratinocytes showed reduced proliferation in vivo by about 40%. Likewise, isolated keratinocytes exhibited reduced proliferation rates in vitro, which could be completely rescued by either exogenously added recombinant sAPPα, or by co-culture with dermal fibroblasts derived from APP knockout mice. Moreover, APP-knockout keratinocytes revealed reduced migration velocity resulting from severely compromised cell substrate adhesion. Keratinocytes from double knockout mice died within the first week of culture, indicating essential functions of APP-family members for survival in vitro. Our data indicate that sAPPα has to be considered as an essential epidermal growth factor which, however, in vivo can be functionally compensated to a certain extent by other growth factors, e.g., factors released from dermal fibroblasts.