Keratinocytes from APP/APLP2-deficient mice are impaired in proliferation, adhesion and migration in vitro.
Growing evidence shows that the soluble N-terminal form (sAPPalpha) 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 sAPPalpha, 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 sAPPalpha 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.
Institute of Cell Biology and Bonner Forum Biomedizin, University of Bonn, Ulrich-Haberlandstr. 61A, 53121 Bonn, Germany.
Christina
C
Siemes
Thomas
T
Quast
Christiane
C
Kummer
Sven
S
Wehner
Gregor
G
Kirfel
Ulrike
U
Müller
Volker
V
Herzog
D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018715:Microscopy, Video; D011994:Recombinant Proteins / Q000235:genetics
D016564:Amyloid beta-Protein Precursor; C492952:Aplp2 protein, mouse; D011994:Recombinant Proteins