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

A Colombo, HE Hsia, M Wang, PH Kuhn, MS Brill, P Canevazzi, R Feederle, C Taveggia, T Misgeld, SF Lichtenthaler

Research output: Contribution to journalArticle

Abstract

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 in vitro 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 in vitro 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. © 2018 The Authors
Original languageEnglish
Article numbere97390
JournalEMBO Journal
Volume37
Issue number7
Publication statusPublished - 2018

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Death Domain Receptors
Schwann Cells
Cell proliferation
Cell Proliferation
Peripheral Nervous System
Neurology
Assays
Paracrine Communication
Disintegrins
Tumor Necrosis Factor Receptors
Metalloproteases
Cell death
Knockout Mice
Neurons
Cell Differentiation
Cell Death
Cells
Phenotype

Cite this

Colombo, A., Hsia, HE., Wang, M., Kuhn, PH., Brill, MS., Canevazzi, P., ... Lichtenthaler, SF. (2018). Non-cell-autonomous function of DR6 in Schwann cell proliferation. EMBO Journal, 37(7), [e97390].

Non-cell-autonomous function of DR6 in Schwann cell proliferation. / Colombo, A; Hsia, HE; Wang, M; Kuhn, PH; Brill, MS; Canevazzi, P; Feederle, R; Taveggia, C; Misgeld, T; Lichtenthaler, SF.

In: EMBO Journal, Vol. 37, No. 7, e97390, 2018.

Research output: Contribution to journalArticle

Colombo, A, Hsia, HE, Wang, M, Kuhn, PH, Brill, MS, Canevazzi, P, Feederle, R, Taveggia, C, Misgeld, T & Lichtenthaler, SF 2018, 'Non-cell-autonomous function of DR6 in Schwann cell proliferation', EMBO Journal, vol. 37, no. 7, e97390.
Colombo A, Hsia HE, Wang M, Kuhn PH, Brill MS, Canevazzi P et al. Non-cell-autonomous function of DR6 in Schwann cell proliferation. EMBO Journal. 2018;37(7). e97390.
Colombo, A ; Hsia, HE ; Wang, M ; Kuhn, PH ; Brill, MS ; Canevazzi, P ; Feederle, R ; Taveggia, C ; Misgeld, T ; Lichtenthaler, SF. / Non-cell-autonomous function of DR6 in Schwann cell proliferation. In: EMBO Journal. 2018 ; Vol. 37, No. 7.
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AB - 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 in vitro 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 in vitro 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. © 2018 The Authors

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