dSarm/Sarm1 Is Required for Activation of an Injury-Induced Axon Death Pathway

Osterloh, Jeannette M.; Yang, Jing; Rooney, Timothy M.; Fox, A. Nicole; Adalbert, Róbert; Powell, Eric; Sheehan, Amy E.; Avery, Michelle A.; Hackett, Rachel; Logan, Mary A.; MacDonald, Jennifer M.; Ziegenfuss, Jennifer S.; Milde, Stefan; Hou, Yanming; Nathan, Carl; Ding, Aihao; Brown, Robert H.; Conforti, Laura; Coleman, Michael P.; Tessier‐Lavigne, Marc; Züchner, Stephan; Freeman, Marc

doi:10.1126/science.1223899

Cited by 579 publications

(700 citation statements)

References 31 publications

(33 reference statements)

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“…Genetic mutants in invertebrates and vertebrates demonstrated that injury induces an active axon destruction program (Mack et al, 2001;McDonald et al, 2006;Osterloh et al, 2012;Gilley et al, 2015). Schwann cells in the distal nerve stump lose their axonal attachment, proliferate and resorb myelin.…”

Section: Nrg1 and Remyelination After Injurymentioning

confidence: 99%

Neuregulin/ErbB Signaling in Developmental Myelin Formation and Nerve Repair

Birchmeier

Bennett

2016

Current Topics in Developmental Biology

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Myelin is essential for rapid and accurate conduction of electrical impulses by axons in the central and peripheral nervous system. Myelin is formed in the early postnatal period, and developmental myelination in the peripheral nervous system (PNS) depends on axonal signals provided by Nrg1/ErbB receptors. In addition, Nrg1 is required for effective nerve repair and remyelination in adulthood. We discuss here similarities and differences in Nrg1/ErbB functions in developmental myelination and remyelination after nerve injury.

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Section: Nrg1 and Remyelination After Injurymentioning

confidence: 99%

Neuregulin/ErbB Signaling in Developmental Myelin Formation and Nerve Repair

Birchmeier

Bennett

2016

Current Topics in Developmental Biology

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“…4 A and B). Thus, axon death in the L1 vein requires dsarm function, similarly to sensory neurons in antennae, and multiple neuronal subtypes in mammals (12).…”

Section: A Tool Kit For Rapid Genome-wide Forward Genetic Screens Withmentioning

confidence: 99%

“…Recently, we described the first forward genetic screen for loss-of-function mutations capable of blocking WD in Drosophila, and identified the kinase scaffolding molecule dSarm/Sarm1 (sterile alpha/Armadillo/Tollinterleukin receptor homology domain protein) as essential for WD in both the fly and mouse in vivo (12). Thus, unbiased genetic screens in Drosophila can lead to the identification of key genes required for mammalian axon degeneration after injury.…”

mentioning

confidence: 99%

Rapid in vivo forward genetic approach for identifying axon death genes in Drosophila

Neukomm

Burdett

Gonzalez

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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124

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Axons damaged by acute injury, toxic insults, or neurodegenerative diseases execute a poorly defined autodestruction signaling pathway leading to widespread fragmentation and functional loss. Here, we describe an approach to study Wallerian degeneration in the Drosophila L1 wing vein that allows for analysis of axon degenerative phenotypes with single-axon resolution in vivo. This method allows for the axotomy of specific subsets of axons followed by examination of progressive axonal degeneration and debris clearance alongside uninjured control axons. We developed new Flippase (FLP) reagents using proneural gene promoters to drive FLP expression very early in neural lineages. These tools allow for the production of mosaic clone populations with high efficiency in sensory neurons in the wing. We describe a collection of lines optimized for forward genetic mosaic screens using MARCM (mosaic analysis with a repressible cell marker; i.e., GFPlabeled, homozygous mutant) on all major autosomal arms (∼95% of the fly genome). Finally, as a proof of principle we screened the X chromosome and identified a collection eight recessive and two dominant alleles of highwire, a ubiquitin E3 ligase required for axon degeneration. Similar unbiased forward genetic screens should help rapidly delineate axon death genes, thereby providing novel potential drug targets for therapeutic intervention to prevent axonal and synaptic loss.neurodegeneration | glial response W idespread axonal degeneration and synapse loss occurs during neurodegenerative disease and after neural trauma. These degradative events result in disruption of neural circuit connectivity and ultimately functional impairment of the nervous system. Identifying molecular cascades that actively promote axonal self-destruction is a key goal. However, despite decades of work, remarkably little is known about the molecular pathways that drive the degeneration of neurites or synapses in any context (1, 2).Axotomy-induced axon degeneration (termed Wallerian degeneration, WD) serves as a useful model to study the mechanisms of axonal self-destruction. When axons are severed, the portion of the axon distal to the injury site and its synapses undergo catastrophic fragmentation after a defined latent phase, and the resulting debris is eventually cleared by surrounding glial cells. The discovery of the spontaneous Wallerian degeneration slow (Wld S ) mouse revealed, surprisingly, that severed axons can in fact survive for weeks in the absence of a cell body (3). It also led to the proposal that "axon death" signaling cascades might exist, akin to apoptotic cell death programs, which actively drive the destruction of the axon (4).Interestingly, Wld S provides significant suppression in mouse models of progressive motor neuron disease and glaucoma (5-8), and moderate protection from chemotherapy-induced axon degeneration (9). These observations argue that defining the molecular mechanisms of axon degeneration in the context of WD could have an important therapeutic impact on the treat...

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“…Genetic screens in invertebrate and vertebrate model systems identified the Sterile alpha and Toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) as a conserved, fundamental executioner of pathological axon destruction (2,3). After nerve injury, SARM1 is required for the precipitous loss of the metabolite NAD + (4).…”

mentioning

confidence: 99%

SARM1-specific motifs in the TIR domain enable NAD ⁺ loss and regulate injury-induced SARM1 activation

Summers

Gibson

DiAntonio

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

117

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Axon injury in response to trauma or disease stimulates a selfdestruction program that promotes the localized clearance of damaged axon segments. Sterile alpha and Toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) is an evolutionarily conserved executioner of this degeneration cascade, also known as Wallerian degeneration; however, the mechanism of SARM1-dependent neuronal destruction is still obscure. SARM1 possesses a TIR domain that is necessary for SARM1 activity. In other proteins, dimerized TIR domains serve as scaffolds for innate immune signaling. In contrast, dimerization of the SARM1 TIR domain promotes consumption of the essential metabolite NAD + and induces neuronal destruction. This activity is unique to the SARM1 TIR domain, yet the structural elements that enable this activity are unknown. In this study, we identify fundamental properties of the SARM1 TIR domain that promote NAD + loss and axon degeneration. Dimerization of the TIR domain from the Caenorhabditis elegans SARM1 ortholog TIR-1 leads to NAD + loss and neuronal death, indicating these activities are an evolutionarily conserved feature of SARM1 function. Detailed analysis of sequence homology identifies canonical TIR motifs as well as a SARM1-specific (SS) loop that are required for NAD + loss and axon degeneration. Furthermore, we identify a residue in the SARM1 BB loop that is dispensable for TIR activity yet required for injury-induced activation of full-length SARM1, suggesting that SARM1 function requires multidomain interactions. Indeed, we identify a physical interaction between the autoinhibitory N terminus and the TIR domain of SARM1, revealing a previously unrecognized direct connection between these domains that we propose mediates autoinhibition and activation upon injury.A xon degeneration in response to injury or disease is a hallmark of neurological disorders of the peripheral and central nervous systems. Akin to programmed cell death pathways, such as apoptosis, axon injury in response to disease or trauma stimulates a local signaling cascade that executes destruction of the injured axon segment (1). Despite growing attention, the molecular details of this prodegenerative cascade are still unclear. A more substantial understanding of the molecular factors that participate in this axon destructive process will likely provide new therapeutic strategies for peripheral neuropathies and other neurodegenerative conditions.Genetic screens in invertebrate and vertebrate model systems identified the Sterile alpha and Toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) as a conserved, fundamental executioner of pathological axon destruction (2, 3). After nerve injury, SARM1 is required for the precipitous loss of the metabolite NAD + (4). Augmenting NAD + biosynthetic pathways protects injured axons from degeneration, suggesting this step is crucial in axonal breakdown (5, 6). In addition to local axon degeneration, SARM1 promotes neuronal cell death in response to mitochondrial toxins, oxygen gluc...

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dSarm/Sarm1 Is Required for Activation of an Injury-Induced Axon Death Pathway

Cited by 579 publications

References 31 publications

Neuregulin/ErbB Signaling in Developmental Myelin Formation and Nerve Repair

Neuregulin/ErbB Signaling in Developmental Myelin Formation and Nerve Repair

Rapid in vivo forward genetic approach for identifying axon death genes in Drosophila

SARM1-specific motifs in the TIR domain enable NAD ⁺ loss and regulate injury-induced SARM1 activation

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dSarm/Sarm1 Is Required for Activation of an Injury-Induced Axon Death Pathway

Cited by 579 publications

References 31 publications

Neuregulin/ErbB Signaling in Developmental Myelin Formation and Nerve Repair

Neuregulin/ErbB Signaling in Developmental Myelin Formation and Nerve Repair

Rapid in vivo forward genetic approach for identifying axon death genes in Drosophila

SARM1-specific motifs in the TIR domain enable NAD + loss and regulate injury-induced SARM1 activation

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SARM1-specific motifs in the TIR domain enable NAD ⁺ loss and regulate injury-induced SARM1 activation