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Colombo, A.* ; Hsia, H.E.* ; Wang, M.* ; Kuhn, P.H.* ; Brill, M.S.* ; Canevazzi, P.* ; Feederle, R. ; Taveggia, C.* ; Misgeld, T.* ; Lichtenthaler, S.F.*

Non-cell-autonomous function of DR6 in Schwann cell proliferation.

EMBO J. 37:e97390 (2018)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Death receptor 6 (DR6) is an orphan member of the TNF receptor superfamily and controls cell death and differentiation in a cell-autonomous manner in different cell types. Here, we report an additional non-cell-autonomous function for DR6 in the peripheral nervous system (PNS). DR6-knockout (DR6 KO) mice showed precocious myelination in the PNS. Using an invitro myelination assay, we demonstrate that neuronal DR6 acts in trans on Schwann cells (SCs) and reduces SC proliferation and myelination independently of its cytoplasmic death domain. Mechanistically, DR6 was found to be cleaved in neurons by a disintegrin and metalloprotease 10 (ADAM10), releasing the soluble DR6 ectodomain (sDR6). Notably, in the invitro myelination assay, sDR6 was sufficient to rescue the DR6 KO phenotype. Thus, in addition to the cell-autonomous receptor function of full-length DR6, the proteolytically released sDR6 can unexpectedly also act as a paracrine signaling factor in the PNS in a non-cell-autonomous manner during SC proliferation and myelination. This new mode of DR6 signaling will be relevant in future attempts to target DR6 in disease settings.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Adam10 ; Dr6 ; Myelin ; Schwann Cell ; Shedding; Amyloid Precursor Protein; Neurite Outgrowth; Alpha-secretase; In-vivo; Death; Adam10; Neuregulin-1; Myelination; Neurons; Bace1
Sprache englisch
Veröffentlichungsjahr 2018
HGF-Berichtsjahr 2018
ISSN (print) / ISBN 0261-4189
e-ISSN 1460-2075
Zeitschrift EMBO Journal, The
Quellenangaben Band: 37, Heft: 7, Seiten: , Artikelnummer: e97390 Supplement: ,
Verlag Wiley
Verlagsort Heidelberg, Germany
Begutachtungsstatus Peer reviewed
Institut(e) CF Monoclonal Antibodies (CF-MAB)
POF Topic(s) 30201 - Metabolic Health
Forschungsfeld(er) Helmholtz Diabetes Center
PSP-Element(e) G-502210-001
DOI 10.15252/embj.201797390
WOS ID WOS:000429008200001
Scopus ID 85042119726
PubMed ID 29459438
Erfassungsdatum 2018-05-22
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