title: The disintegrin/metalloproteinase Adam10 is essential for epidermal integrity and Notch-mediated signaling.
abstract: The disintegrin and metalloproteinase Adam10 has been implicated in the regulation of key signaling pathways that determine skin morphogenesis and homeostasis. To address the in vivo relevance of Adam10 in the epidermis, we have selectively disrupted Adam10 during skin morphogenesis and in adult skin. K14-Cre driven epidermal Adam10 deletion leads to perinatal lethality, barrier impairment and absence of sebaceous glands. A reduction of spinous layers, not associated with differences in either proliferation or apoptosis, indicates that loss of Adam10 triggers a premature differentiation of spinous keratinocytes. The few surviving K14-Adam10-deleted mice and mice in which Adam10 was deleted postnatally showed loss of hair, malformed vibrissae, epidermal hyperproliferation, cyst formation, thymic atrophy and upregulation of the cytokine thymic stromal lymphopoetin (TSLP), thus indicating non cell-autonomous multi-organ disease resulting from a compromised barrier. Together, these phenotypes closely resemble skin specific Notch pathway loss-of-function phenotypes. Notch processing is indeed strongly reduced resulting in decreased levels of Notch intracellular domain fragment and functional Notch signaling. The data identify Adam10 as the major Site-2 processing enzyme for Notch in the epidermis in vivo, and thus as a central regulator of skin development and maintenance.
authors.affiliation: Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, Kiel, Germany.
authors.forename: Silvio
authors.initials: S
authors.lastname: Weber
authors.forename: Michaela T
authors.initials: MT
authors.lastname: Niessen
authors.forename: Johannes
authors.initials: J
authors.lastname: Prox
authors.forename: Renate
authors.initials: R
authors.lastname: Lüllmann-Rauch
authors.forename: Annika
authors.initials: A
authors.lastname: Schmitz
authors.forename: Ralf
authors.initials: R
authors.lastname: Schwanbeck
authors.forename: Carl P
authors.initials: CP
authors.lastname: Blobel
authors.forename: Ellen
authors.initials: E
authors.lastname: Jorissen
authors.forename: Bart
authors.initials: B
authors.lastname: de Strooper
authors.forename: Carien M
authors.initials: CM
authors.lastname: Niessen
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism*; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D020411:Oligonucleotide Array Sequence Analysis; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D008565:Membrane Proteins; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse