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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)
Publ. Version/Full Text Research data DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Adam10 ; Dr6 ; Myelin ; Schwann Cell ; Shedding; Amyloid Precursor Protein; Neurite Outgrowth; Alpha-secretase; In-vivo; Death; Adam10; Neuregulin-1; Myelination; Neurons; Bace1
ISSN (print) / ISBN 0261-4189
e-ISSN 1460-2075
Journal EMBO Journal, The
Quellenangaben Volume: 37, Issue: 7, Pages: , Article Number: e97390 Supplement: ,
Publisher Wiley
Publishing Place Heidelberg, Germany
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) CF Monoclonal Antibodies (CF-MAB)