title: The c-Jun kinase signaling cascade promotes glial engulfment activity through activation of draper and phagocytic function.
abstract: After neuronal injury or death glial cells become reactive, exhibiting dramatic changes in morphology and patterns of gene expression and ultimately engulfing neuronal debris. Rapid clearance of degenerating neuronal material is thought to be crucial for suppression of inflammation and promotion of functional recovery. Here we demonstrate that Drosophila c-Jun N-terminal kinase (dJNK) signaling is a critical in vivo mediator of glial engulfment activity. In response to axotomy, we find glial dJNK signals through a cascade involving the upstream mitogen-activated protein kinase kinase kinases Slipper and Tak1, the mitogen-activated protein kinase kinase MKK4, and ultimately the Drosophila activator protein 1 (AP-1) transcriptional complex composed of Jra and Kayak to initiate glial phagocytosis of degenerating axons. Interestingly, loss of dJNK also blocked injury-induced upregulation of Draper levels in glia, and glial-specific overexpression of Draper was sufficient to rescue engulfment defects associated with loss of dJNK signaling. This work identifies that the dJNK pathway is a novel mediator of glial engulfment activity and a primary role for the glial Slipper/Tak1 →MKK4 →dJNK →dAP-1 signaling cascade appears to be activation of draper expression after axon injury.
authors.affiliation: Department of Neurobiology, University of Massachusetts Medical School, Howard Hughes Medical Institute, Worcester, MA 01605, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Macdonald
authors.forename: J
authors.initials: J
authors.lastname: Doherty
authors.forename: R
authors.initials: R
authors.lastname: Hackett
authors.forename: M R
authors.initials: MR
authors.lastname: Freeman
mesh_terms: D000818:Animals; D017209:Apoptosis; D001369:Axons / Q000378:metabolism; D019771:Axotomy; D001921:Brain / Q000378:metabolism; D001930:Brain Injuries / Q000235:genetics / Q000378:metabolism; D004330:Drosophila; D029721:Drosophila Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism*; D010587:Phagocytosis / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; C495322:drpr protein, Drosophila; C435749:kay protein, Drosophila; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C447860:slpr protein, Drosophila; D048670:MAP Kinase Kinase 4