During the normal development of the mammalian nervous system there is extensive programmed cell death, which is required for establishing proper cell numbers and connections. A number of pathologies, such as nerve injury and diseases such as Alzheimer's can lead to apoptosis as well. The resulting neuronal corpses must be efficiently removed in order to prevent an immune system response, which can involve inflammation and autoimmunity. Indeed, a number of autoimmune diseases have been associated with a failure to properly clear dead cells. Unfortunately, the molecular mechanisms underlying this phagocytic process are poorly understood, particularly in the nervous system. In the peripheral nervous system, there is virtually nothing known about how the dead neurons are removed. Hence, the overall goal of this study is to elucidate the cellular and molecular mechanisms underlying the phagocytosis of apoptotic neurons in the developing peripheral nervous system. In C. elegans, two pathways involved in apoptotic cell clearance have been genetically defined;the first includes CED-1, -6, -7 and -10 and the second CED-2, -5, -10 and -12. The mammalian homologs of most of these genes have been identified;however, for CED-1, which is thought to function as a receptor for cell corpses, there have been several possible homologs proposed, including MEGF10, LRP-1 and the scavenger receptor SREC, but no consensus has been reached. Whether these pathways participate in the removal of apoptotic neurons during mammalian development is not known. Our preliminary data suggest that MEGF10 and a related protein, Jedi, are required for dorsal root ganglia (DRG) neuron engulfment and that satellite cells in the ganglia express these genes and are responsible for the removal of the dead neurons. Therefore, we hypothesize that the phagocytosis of dead DRG neurons during embryogenesis by satellite cells involves the putative CED-1 homologs MEGF10 and Jedi. To address this hypothesis we propose the following specific aims: (1) Determine whether MEGF10 and/or Jedi functions as a receptor for apoptotic neuron engulfment by satellite cells;(2) Define the expression pattern of MEGF10 and Jedi in the developing mouse;(3) Determine whether Jedi or MEGF10 signal through homologs of the CED-1 pathway to regulate Rac;(4) Determine whether Jedi is required in vivo for neuronal corpse engulfment during development. Elucidating the mechanisms by which apoptotic neurons are phagocytosed will not only enhance our understanding of the development of the mammalian nervous system, but will likely provide important insights into the etiology of autoimmune neuropathies.
Neuronal cell death is a normal part of the development of the mammalian nervous system, required for establishing proper cell numbers and connections, but can also occur in various injuries and neuropathologies;for example, stroke, Alzheimer's disease and chemotherapeutic treatment. The failure to remove dead cells can lead to an inflammatory response and autoimmune diseases;however, how these dead neurons are cleared is not well understood and in the peripheral nervous system is completely unknown. The goal of this application is to determine the cellular and molecular mechanisms underlying the clearance of dead neurons in the developing peripheral nervous system.
|Sullivan, Chelsea S; Scheib, Jami L; Ma, Zhong et al. (2014) The adaptor protein GULP promotes Jedi-1-mediated phagocytosis through a clathrin-dependent mechanism. Mol Biol Cell 25:1925-36|
|Guo, Jiasong; Wang, Leiming; Zhang, Yang et al. (2014) Abnormal junctions and permeability of myelin in PMP22-deficient nerves. Ann Neurol 75:255-65|
|Limpert, Allison S; Bai, Shujun; Narayan, Malathi et al. (2013) NF-ÎºB forms a complex with the chromatin remodeler BRG1 to regulate Schwann cell differentiation. J Neurosci 33:2388-97|
|Hermanson, Daniel J; Hartley, Nolan D; Gamble-George, Joyonna et al. (2013) Substrate-selective COX-2 inhibition decreases anxiety via endocannabinoid activation. Nat Neurosci 16:1291-8|
|Benesh, Andrew E; Fleming, Jonathan T; Chiang, Chin et al. (2012) Expression and localization of myosin-1d in the developing nervous system. Brain Res 1440:9-22|
|Scheib, Jami L; Sullivan, Chelsea S; Carter, Bruce D (2012) Jedi-1 and MEGF10 signal engulfment of apoptotic neurons through the tyrosine kinase Syk. J Neurosci 32:13022-31|
|Duggan, Kelsey C; Hermanson, Daniel J; Musee, Joel et al. (2011) (R)-Profens are substrate-selective inhibitors of endocannabinoid oxygenation by COX-2. Nat Chem Biol 7:803-9|
|Limpert, Allison S; Carter, Bruce D (2010) Axonal neuregulin 1 type III activates NF-kappaB in Schwann cells during myelin formation. J Biol Chem 285:16614-22|
|Scheib, Jami L; Carter, Bruce D (2010) Eaters of the dead: glial precursors clear neuron corpses during development. Cell Cycle 9:1867-8|
|Wu, Hsiao-Huei; Bellmunt, Elena; Scheib, Jami L et al. (2009) Glial precursors clear sensory neuron corpses during development via Jedi-1, an engulfment receptor. Nat Neurosci 12:1534-41|