title: The Rag-Ragulator Complex Regulates Lysosome Function and Phagocytic Flux in Microglia.
abstract: Microglia are resident macrophages of the CNS that are essential for phagocytosis of apoptotic neurons and weak synapses during development. We show that RagA and Lamtor4, two components of the Rag-Ragulator complex, are essential regulators of lysosomes in microglia. In zebrafish lacking RagA function, microglia exhibit an expanded lysosomal compartment, but they are unable to properly digest apoptotic neuronal debris. Previous biochemical studies have placed the Rag-Ragulator complex upstream of mTORC1 activation in response to cellular nutrient availability. Nonetheless, RagA and mTOR mutant zebrafish have distinct phenotypes, indicating that the Rag-Ragulator complex has functions independent of mTOR signaling. Our analysis reveals an essential role of the Rag-Ragulator complex in proper lysosome function and phagocytic flux in microglia.
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Kimberle
authors.initials: K
authors.lastname: Shen
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Harwin
authors.initials: H
authors.lastname: Sidik
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: william.talbot@stanford.edu.
authors.forename: William S
authors.initials: WS
authors.lastname: Talbot
mesh_terms: D000818:Animals; D004252:DNA Mutational Analysis; D004625:Embryo, Nonmammalian / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D017403:In Situ Hybridization; D008247:Lysosomes / Q000378:metabolism*; D017628:Microglia / Q000378:metabolism*; D018613:Microscopy, Confocal; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D016296:Mutagenesis; D010587:Phagocytosis; D010641:Phenotype; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000254:growth & development / Q000378:metabolism; D029961:Zebrafish Proteins / Q000378:metabolism*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D029961:Zebrafish Proteins; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins