Death Receptor 6 Promotes Wallerian Degeneration in Peripheral Axons

Gamage, Kanchana K.; Cheng, Irene H.; Park, Rachel E.; Karim, Mardeen S.; Edamura, Kazusa; Hughes, Christopher C.W.; Spano, Anthony; Erişir, Alev; Deppmann, Christopher D.

doi:10.1016/j.cub.2017.01.062

Cited by 36 publications

(53 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…At P7 and P21, the number of myelinated fibers per area was increased compared to P1, but was no longer different between WT and DR6 KO, indicating that DR6 deficiency induces a precocious myelination in early postnatal development. It is possible that the axon diameters increase even further in adulthood as recently described (Gamage et al, 2017). The mild, but not significant increase of the averaged g-ratio (0.718 in WT versus 0.734 in DR6 KO) was particularly seen for axons with large diameters (> 3 lm) but not for axons with smaller diameters (Fig 3D).…”

Section: Dr6 Controls Pns Myelinationsupporting

confidence: 56%

“…For the PNS, we report a non-cellautonomous mechanism of DR6 signaling, whereas in the CNS, DR6 acts in cis in a cell-autonomous manner in oligodendrocytes (Mi et al, 2011). Notably, this reduction of the g-ratio is not anymore seen in adult DR6 KO mice both in the CNS (Mi et al, 2011) and in the PNS (Gamage et al, 2017). DR6 deficiency did not alter the g-ratio in the PNS of very young mice at P7 in our study, but lowered the g-ratio in the CNS by 15% at P15 (Mi et al, 2011).…”

Section: Discussionmentioning

confidence: 70%

“…One family member, where proteolysis and its functional consequence have been little studied (Tam et al, 2004;DeRosa et al, 2008), is death receptor 6 (DR6, TNFRSF21). In neurons and oligodendrocytes, full-length DR6 acts as a receptor that activates cell death pathways, resulting in developmental axon pruning, Wallerian degeneration, and reduced oligodendrocyte-mediated myelination in the CNS (Nikolaev et al, 2009;Mi et al, 2011;Marik et al, 2013;Gamage et al, 2017). DR6 is also expressed in oligodendrocytes, which are the myelinating cells in the CNS.…”

Section: Introductionmentioning

confidence: 99%

“…DR6 is also expressed in oligodendrocytes, which are the myelinating cells in the CNS. In neurons and oligodendrocytes, full-length DR6 acts as a receptor that activates cell death pathways, resulting in developmental axon pruning, Wallerian degeneration, and reduced oligodendrocyte-mediated myelination in the CNS (Nikolaev et al, 2009;Mi et al, 2011;Marik et al, 2013;Gamage et al, 2017). Consequently, DR6 has been linked to Alzheimer's disease and is considered as a drug target for multiple sclerosis (Nikolaev et al, 2009;Mi et al, 2011;Kallop et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2018

View full text Add to dashboard Cite

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 myelination assay, we demonstrate that neuronal DR6 acts in 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 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.

show abstract

Section: Dr6 Controls Pns Myelinationsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2018

View full text Add to dashboard Cite

show abstract

“…This is reminiscent of death receptor 6, a member of the TNF receptor superfamily. Full-length DR6 can act as a surface receptor transmitting cell death signals (Nikolaev et al, 2009;Mi et al, 2011;Strilic et al, 2016;Fujikura et al, 2017;Gamage et al, 2017), while the ADAM10-cleaved DR6 ectodomain can act as a cytokine suppressing proliferation of Schwann cells and delaying myelination in the peripheral nervous system (Colombo et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Nr CAM is a marker for substrate‐selective activation of ADAM 10 in Alzheimer's disease

et al. 2019

View full text Add to dashboard Cite

The metalloprotease ADAM 10 is a drug target in Alzheimer's disease, where it cleaves the amyloid precursor protein ( APP ) and lowers amyloid‐beta. Yet, ADAM 10 has additional substrates, which may cause mechanism‐based side effects upon therapeutic ADAM 10 activation. However, they may also serve—in addition to APP —as biomarkers to monitor ADAM 10 activity in patients and to develop APP ‐selective ADAM 10 activators. Our study demonstrates that one such substrate is the neuronal cell adhesion protein Nr CAM . ADAM 10 controlled Nr CAM surface levels and regulated neurite outgrowth in vitro in an Nr CAM ‐dependent manner. However, ADAM 10 cleavage of Nr CAM , in contrast to APP , was not stimulated by the ADAM 10 activator acitretin, suggesting that substrate‐selective ADAM 10 activation may be feasible. Indeed, a whole proteome analysis of human CSF from a phase II clinical trial showed that acitretin, which enhanced APP cleavage by ADAM 10, spared most other ADAM 10 substrates in brain, including Nr CAM . Taken together, this study demonstrates an Nr CAM ‐dependent function for ADAM 10 in neurite outgrowth and reveals that a substrate‐selective, therapeutic ADAM 10 activation is possible and may be monitored with Nr CAM .

show abstract

Injury and Self‐Repair of Musculoskeletal Tissues

2022

Musculoskeletal Disorders

View full text Add to dashboard Cite

Death Receptor 6 Promotes Wallerian Degeneration in Peripheral Axons

Abstract: Graphical abstract

Cited by 36 publications

References 41 publications

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

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

Nr CAM is a marker for substrate‐selective activation of ADAM 10 in Alzheimer's disease

Injury and Self‐Repair of Musculoskeletal Tissues

Contact Info

Product

Resources

About