title: Knockdown of the Drosophila FIG4 induces deficient locomotive behavior, shortening of motor neuron, axonal targeting aberration, reduction of life span and defects in eye development.
abstract: Mutations in Factor-Induced-Gene 4 (FIG4) gene have been identified in Charcot-Marie-Tooth disease type 4J (CMT4J), Yunis-Varon syndrome and epilepsy with polymicrogyria. FIG4 protein regulates a cellular abundance of phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), a signaling lipid on the cytosolic surface of membranes of the late endosomal compartment. PI(3,5)P2 is required for retrograde membrane trafficking from lysosomal and late endosomal compartments to the Golgi. However, it is still unknown how the neurodegeneration that occurs in these diseases is related to the loss of FIG4 function. Drosophila has CG17840 (dFIG4) as a human FIG4 homolog. Here we specifically knocked down dFIG4 in various tissues, and investigated their phenotypes. Neuron-specific knockdown of dFIG4 resulted in axonal targeting aberrations of photoreceptor neurons, shortened presynaptic terminals of motor neurons in 3rd instar larvae and reduced climbing ability in adulthood and life span. Fat body-specific knockdown of dFIG4 resulted in enlarged lysosomes in cells that were detected by staining with LysoTracker. In addition, eye imaginal disk-specific knockdown of dFIG4 disrupted differentiation of pupal ommatidial cell types, such as cone cells and pigment cells, suggesting an additional role of dFIG4 during eye development.
authors.affiliation: Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan; The Center for Advanced Insect Research, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan.
authors.forename: Akane
authors.initials: A
authors.lastname: Kyotani
authors.affiliation: Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Azuma
authors.affiliation: Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan; The Center for Advanced Insect Research, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan.
authors.forename: Itaru
authors.initials: I
authors.lastname: Yamamoto
authors.affiliation: Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan; The Center for Advanced Insect Research, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Mizuta
authors.affiliation: Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Mizuno
authors.affiliation: North Medical Center, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakagawa
authors.affiliation: Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan; Department of Molecular Pathobiology of Brain Diseases, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Tokuda
authors.affiliation: Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan; The Center for Advanced Insect Research, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan. Electronic address: myamaguc@kit.ac.jp.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Yamaguchi
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001369:Axons / Q000473:pathology*; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D005124:Eye Abnormalities / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005420:Flavoproteins / Q000235:genetics; D020233:Gait Disorders, Neurologic / Q000235:genetics* / Q000473:pathology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D060227:Imaginal Discs / Q000473:pathology; D008136:Longevity / Q000235:genetics*; D008247:Lysosomes / Q000473:pathology; D009046:Motor Neurons / Q000473:pathology*; D009469:Neuromuscular Junction / Q000235:genetics / Q000473:pathology; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency* / Q000235:genetics; D017956:Photoreceptor Cells, Invertebrate / Q000473:pathology; D011596:Psychomotor Disorders / Q000235:genetics; D016415:Sequence Alignment
chemical_list: D029721:Drosophila Proteins; D005420:Flavoproteins; D049452:Green Fluorescent Proteins; C522215:FIG4 protein, human; D010744:Phosphoric Monoester Hydrolases
keywords: CMT4J; Drosophila; Eye; FIG4; Neuron