The disintegrin/metalloproteinase Adam10 is essential for epidermal integrity and Notch-mediated signaling

Abstract

SUMMARYThe 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.

Shedding of Endogenous Interleukin-6 Receptor (IL-6R) Is Governed by A Disintegrin and Metalloproteinase (ADAM) Proteases while a Full-length IL-6R Isoform Localizes to Circulating Microvesicles

“…4B). ADAM8 and ADAM10 exhibit overlapping substrate spectra, as exemplified by cleavage of CD23 (36), while ADAM8 expression in mouse skin is strongly up-regulated in the absence of ADAM10 (37). We speculated that ADAM8 might likewise compensate for the loss of ADAM10 in myeloid cells, but observed similar sIL-6R serum levels in ADAM8 knock-out mice as compared to wild type animals (Fig.…”

The ADAM family

“…ADAM17 expression was not upregulated, and although ADAM8 expression was reportedly upregulated in Adam10 2/2 keratinocytes, this protease also did not restore Notch cleavage to wild-type levels. 29 These data provide some of the first clear examples of specific ADAM metalloprotease function in specific Notch pathways in vivo; however, the manner in which ADAM10 or 17 is selected for activity in Notch signaling in vivo is largely unknown. A potential explanation comes from studies by Bozkulak and Weinmaster and van Tetering et al, 14,33 which show that ADAM10 Notch cleavage is ligand-dependent while ADAM17 activates Notch in a ligand-independent manner in a mammalian cell culture-based system.…”

“…34 ADAM17 was detected by Zhang et al and Weber et al in the mouse heart and epidermis using real-time reverse transcriptase PCR and Western blotting, respectively. 28,29 The presence of ADAM17 in mammalian tissues requiring ADAM10 suggests that tissuerestricted expression of different ADAMs may not be the major regulator of ADAM protein function. However, the amount of ADAM17 in these tissues was not quantified relative to ADAM10 or to ADAM17 expression in other tissues.…”

“…21,26,27 Recently, Zhang et al and Weber et al have reported that ADAM10 is essential for Notch-mediated signaling in the mouse cardiovascular system and epidermis, respectively. 28,29 During cardiovascular development in mice, flies and frogs, Notch activation inhibits cardiomyocyte formation. Notch activation also stimulates epithelial to mesenchymal transition (EMT) of endocardial cells in vertebrates, which invade the cardiac jelly to form an endocardial cushion and eventually valve structures.…”

“…31,32 In order to study ADAM10 specifically in the epidermis, Weber et al 29 deleted the entire gene in the epidermis, hair follicles, and sebaceous glands. These mice phenocopied those with conditional epidermal Notch1/Notch2 knockouts and almost all of the resulting Adam10 epi2/2 mice died less than 24 h after birth due to failure of their epidermis to retain water.…”