title: Autophagy linked FYVE (Alfy/WDFY3) is required for establishing neuronal connectivity in the mammalian brain.
abstract: The regulation of protein degradation is essential for maintaining the appropriate environment to coordinate complex cell signaling events and to promote cellular remodeling. The Autophagy linked FYVE protein (Alfy), previously identified as a molecular scaffold between the ubiquitinated cargo and the autophagic machinery, is highly expressed in the developing central nervous system, indicating that this pathway may have yet unexplored roles in neurodevelopment. To examine this possibility, we used mouse genetics to eliminate Alfy expression. We report that this evolutionarily conserved protein is required for the formation of axonal tracts throughout the brain and spinal cord, including the formation of the major forebrain commissures. Consistent with a phenotype reflecting a failure in axon guidance, the loss of Alfy in mice disrupts localization of glial guidepost cells, and attenuates axon outgrowth in response to Netrin-1. These findings further support the growing indication that macroautophagy plays a key role in the developing CNS.
authors.affiliation: Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, United States.
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Dragich
authors.affiliation: Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, United States.|Department of Cell Biology, College of Physicians and Surgeons, Columbia University, New York, United States.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Kuwajima
authors.affiliation: Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, United States.
authors.forename: Megumi
authors.initials: M
authors.lastname: Hirose-Ikeda
authors.affiliation: Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, United States.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Yoon
authors.affiliation: Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, United States.
authors.forename: Evelien
authors.initials: E
authors.lastname: Eenjes
authors.affiliation: Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, United States.
authors.forename: Joan R
authors.initials: JR
authors.lastname: Bosco
authors.affiliation: Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, United States.|Doctoral Program in Neurobiology and Behavior, Columbia University, New York, United States.
authors.forename: Leora M
authors.initials: LM
authors.lastname: Fox
authors.affiliation: Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Alf H
authors.initials: AH
authors.lastname: Lystad
authors.affiliation: Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, United States.
authors.forename: Tinmarla F
authors.initials: TF
authors.lastname: Oo
authors.affiliation: Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, United States.
authors.forename: Olga
authors.initials: O
authors.lastname: Yarygina
authors.affiliation: The Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Tomohiro
authors.identifier: 0000-0002-3578-9801
authors.initials: T
authors.lastname: Mita
authors.affiliation: Department of Anatomy and Histology, Fukushima Medical University School of Medicine, Fukushima, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Waguri
authors.affiliation: The Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Ichimura
authors.affiliation: The Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Anne
authors.initials: A
authors.lastname: Simonsen
authors.affiliation: Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, United States.|Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, United States.|Department of Cell Biology, College of Physicians and Surgeons, Columbia University, New York, United States.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Burke
authors.affiliation: Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, United States.|Department of Cell Biology, College of Physicians and Surgeons, Columbia University, New York, United States.|Department of Neuroscience, College of Physicians and Surgeons, Columbia University, New York, United States.|Department of Ophthalmology, College of Physicians and Surgeons, Columbia University, New York, United States.
authors.forename: Carol A
authors.identifier: 0000-0001-6253-505X
authors.initials: CA
authors.lastname: Mason
authors.affiliation: Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, United States.|Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, United States.|Department of Cell Biology, College of Physicians and Surgeons, Columbia University, New York, United States.
authors.forename: Ai
authors.identifier: 0000-0002-7059-2449
authors.initials: A
authors.lastname: Yamamoto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000071183:Autophagy-Related Proteins; D001921:Brain / Q000196:embryology*; D055786:Gene Knockout Techniques; D008810:Mice, Inbred C57BL; D009434:Neural Pathways / Q000196:embryology*; D009474:Neurons / Q000502:physiology*; D033921:Vesicular Transport Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D033921:Vesicular Transport Proteins; C496370:Wdfy3 protein, mouse
keywords: Alfy; Autophagy; Wdfy3; axon guidance; cancer biology; corpus callosum; mouse; neurodevelopment; neuroscience