Axon degeneration induces glial responses through Draper-TRAF4-JNK signalling

Abstract

Draper/Ced-1/MEGF-10 is an engulfment receptor that promotes clearance of cellular debris in C. elegans, Drosophila and mammals. Draper signals through an evolutionarily conserved Src family kinase cascade to drive cytoskeletal rearrangements and target engulfment through Rac1. Glia also alter gene expression patterns in response to axonal injury but pathways mediating these responses are poorly defined. We show Draper is cell autonomously required for glial activation of transcriptional reporters after axonal injury. We identify TNF receptor associated factor 4 (TRAF4) as a novel Draper binding partner that is required for reporter activation and phagocytosis of axonal debris. TRAF4 and misshapen (MSN) act downstream of Draper to activate c-Jun N-terminal kinase (JNK) signalling in glia, resulting in changes in transcriptional reporters that are dependent on Drosophila AP-1 (dAP-1) and STAT92E. Our data argue injury signals received by Draper at the membrane are important regulators of downstream transcriptional responses in reactive glia.

Draper‐mediated JNK signaling is required for glial phagocytosis of apoptotic neurons during Drosophila metamorphosis

“…In Drosophila, it is involved in developmental neuronal apoptosis during embryogenesis, but is not the main player in this process (Lee et al, 2006;Shklover et al, 2015). With respect to glial phagocytosis, the dJNK pathway has been previously shown to act downstream of Drpr only in pathological conditions such as following axonal injury in the adult brain (Lu et al, 2017;Macdonald et al, 2013) or adult ventral nerve cord (Purice et al, 2017) or concurrently with excessive neuronal death in the embryonic CNS (Shklover et al, 2015). In the normal embryonic or adult CNS, dJNK signaling is not required for glial phagocytosis (Macdonald et al, 2013;Shklover et al, 2015).…”

“…It has been shown that following axonal injury in the adult brain, Drosophila JNK (dJNK) signaling upregulates Drpr expression in glia, which consequently leads to promotion of glial phagocytosis of degenerating axons (Lu et al, ; Macdonald et al, ). Activation of the dJNK pathway during embryogenesis also increases glial phagocytic ability following neuronal death (Shklover, Mishnaevski, Levy‐Adam, & Kurant, ).…”

“…which consequently leads to promotion of glial phagocytosis of degenerating axons (Lu et al, 2017;Macdonald et al, 2013). Activation of the dJNK pathway during embryogenesis also increases glial phagocytic ability following neuronal death (Shklover, Mishnaevski, Levy-Adam, & Kurant, 2015).…”

Drosophila glia: Few cell types and many conserved functions

“…Ensheathing glial cells also contribute to the phagocytotic clearance of neuronal debris which requires expression of Draper, TNF receptor associated factor 4 (TRAF4) and Simu/Stabilin‐2 (Awasaki et al, ; Doherty, Logan, Taşdemir, & Freeman, ; Kurant, Axelrod, Leaman, & Gaul, ; Logan et al, ; Lu et al, ; MacDonald et al, ; Watts, Schuldiner, Perrino, Larsen, & Luo, ; Ziegenfuss et al, ). In addition, some removal of neuronal debris that accumulates during axonal pruning for example in the mushroom bodies can be mediated by astrocyte‐like glial cells which then, however, use an alternative signaling pathway (Hakim, Yaniv, & Schuldiner, ; Tasdemir‐Yilmaz & Freeman, ).…”

“…The term wrapping glial cell should be used for glial cells encasing only axons. These glial cells are found exclusively in the PNS where they cover the sensory and motor axons in the peripheral nerves.Ensheathing glial cells also contribute to the phagocytotic clearance of neuronal debris which requires expression of Draper, TNF receptor associated factor 4 (TRAF4) and Simu/Stabilin-2(Awasaki et al, 2006; Doherty, Logan, Taşdemir, & Freeman, 2009;Kurant, Axelrod, Leaman, & Gaul, 2008;Logan et al, 2012;Lu et al, 2017; MacDonald et al, 2006; Watts, Schuldiner, Perrino, Larsen, & Luo, 2004; Ziegenfuss et al, 2008…”