Autophagy linked FYVE (Alfy/WDFY3) is required for establishing neuronal connectivity in the mammalian brain
Joanna M Dragich,
Takaaki Kuwajima,
Megumi Hirose-Ikeda,
Michael S Yoon,
Evelien Eenjes,
Joan R Bosco,
Leora M Fox,
Alf H Lystad,
Tinmarla F Oo,
Olga Yarygina,
Tomohiro Mita,
Satoshi Waguri,
Yoshinobu Ichimura,
Masaaki Komatsu,
Anne Simonsen,
Robert E Burke,
Carol A Mason,
Ai Yamamoto
Affiliations
Joanna M Dragich
Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, United States
Takaaki Kuwajima
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
Megumi Hirose-Ikeda
Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, United States
Michael S Yoon
Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, United States
Evelien Eenjes
Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, United States
Joan R Bosco
Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, United States
Leora M Fox
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
Alf H Lystad
Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
Tinmarla F Oo
Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, United States
Olga Yarygina
Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, United States
The Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
Satoshi Waguri
Department of Anatomy and Histology, Fukushima Medical University School of Medicine, Fukushima, Japan
Yoshinobu Ichimura
The Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
Masaaki Komatsu
The Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
Anne Simonsen
Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
Robert E Burke
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
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
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
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.
