Home LiteratureArticle Details
PMID: 17956977 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results in neurodegeneration in mice.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 104 ·No. 44 ·2007-10-30 ·Pages 17518-23

Zhang Y, Zolov SN, Chow CY, Slutsky SG, Richardson SC, Piper RC, Yang B, Nau JJ, Westrick RJ, Morrison SJ, Meisler MH, Weisman LS

Abstract

The signaling lipid, phosphatidylinositol 3,5-bisphosphate (PI(3,5)P(2)), likely functions in multiple signaling pathways. Here, we report the characterization of a mouse mutant lacking Vac14, a regulator of PI(3,5)P(2) synthesis. The mutant mice exhibit massive neurodegeneration, particularly in the midbrain and in peripheral sensory neurons. Cell bodies of affected neurons are vacuolated, and apparently empty spaces are present in areas where neurons should be present. Similar vacuoles are found in cultured neurons and fibroblasts. Selective membrane trafficking pathways, especially endosome-to-TGN retrograde trafficking, are defective. This report, along with a recent report on a mouse with a null mutation in Fig4, presents the unexpected finding that the housekeeping lipid, PI(3,5)P(2), is critical for the survival of neural cells.

MeSH Terms
Animals Gene Expression Regulation Intracellular Signaling Peptides and Proteins/deficiency,genetics,metabolism Membrane Proteins Mice Mice, Knockout Nerve Degeneration/genetics,metabolism,pathology Phosphatidylinositol Phosphates/metabolism Protein Transport Signal Transduction
Chemicals
Intracellular Signaling Peptides and Proteins Membrane Proteins Phosphatidylinositol Phosphates Vac14 protein, mouse phosphatidylinositol 3,5-diphosphate
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Zhang Yanling
Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-2216, USA.
Zolov Sergey N
Chow Clement Y
Slutsky Shalom G
Richardson Simon C
Piper Robert C
Yang Baoli
Nau Johnathan J
Westrick Randal J
Morrison Sean J
Meisler Miriam H
Weisman Lois S
References (45)
45 references, click to expand
  1. Functional dissection of lipid and protein kinase signals of PIKfyve reveals the role of PtdIns 3,5-P2 production for endomembrane integrity.
    J Biol Chem. 2002 Mar 15;277(11):9206-11 PMID: 11714711
  2. Phosphoinositide 5-phosphatase Fig 4p is required for both acute rise and subsequent fall in stress-induced phosphatidylinositol 3,5-bisphosphate levels.
    Eukaryot Cell. 2006 Apr;5(4):723-31 PMID: 16607019
  3. Mutations in PIP5K3 are associated with François-Neetens mouchetée fleck corneal dystrophy.
    Am J Hum Genet. 2005 Jul;77(1):54-63 PMID: 15902656
  4. A novel PtdIns3P and PtdIns(3,5)P2 phosphatase with an inactivating variant in centronuclear myopathy.
    Hum Mol Genet. 2006 Nov 1;15(21):3098-106 PMID: 17008356
  5. Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J.
    Nature. 2007 Jul 5;448(7149):68-72 PMID: 17572665
  6. Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2.
    Nat Genet. 2000 May;25(1):17-9 PMID: 10802647
  7. Osmotic stress-induced increase of phosphatidylinositol 3,5-bisphosphate requires Vac14p, an activator of the lipid kinase Fab1p.
    J Cell Biol. 2002 Mar 18;156(6):1015-28 PMID: 11889142
  8. Mammalian cell morphology and endocytic membrane homeostasis require enzymatically active phosphoinositide 5-kinase PIKfyve.
    J Biol Chem. 2001 Jul 13;276(28):26141-7 PMID: 11285266
  9. Osmotic stress activates phosphatidylinositol-3,5-bisphosphate synthesis.
    Nature. 1997 Nov 13;390(6656):187-92 PMID: 9367158
  10. Disruption of Mtmr2 produces CMT4B1-like neuropathy with myelin outfolding and impaired spermatogenesis.
    J Cell Biol. 2004 Nov 22;167(4):711-21 PMID: 15557122
  11. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease.
    Nat Genet. 2007 Feb;39(2):168-77 PMID: 17220890
  12. Fab1p is essential for PtdIns(3)P 5-kinase activity and the maintenance of vacuolar size and membrane homeostasis.
    J Cell Biol. 1998 Oct 5;143(1):65-79 PMID: 9763421
  13. Production of phosphatidylinositol 5-phosphate by the phosphoinositide 3-phosphatase myotubularin in mammalian cells.
    J Biol Chem. 2004 Feb 20;279(8):7304-12 PMID: 14660569
  14. An animal model for Charcot-Marie-Tooth disease type 4B1.
    Hum Mol Genet. 2005 Dec 1;14(23):3685-95 PMID: 16249189
  15. Platelet-derived growth factor stimulates synthesis of PtdIns(3,4,5)P3 by activating a PtdIns(4,5)P2 3-OH kinase.
    Nature. 1992 Jul 9;358(6382):157-9 PMID: 1319558
  16. PIKfyve controls fluid phase endocytosis but not recycling/degradation of endocytosed receptors or sorting of procathepsin D by regulating multivesicular body morphogenesis.
    Mol Biol Cell. 2003 Nov;14(11):4581-91 PMID: 14551253
  17. A transmembrane ubiquitin ligase required to sort membrane proteins into multivesicular bodies.
    Nat Cell Biol. 2002 Feb;4(2):117-23 PMID: 11788821
  18. Binding of Vac14 to neuronal nitric oxide synthase: Characterisation of a new internal PDZ-recognition motif.
    FEBS Lett. 2006 Dec 22;580(30):6948-54 PMID: 17161399
  19. Structure and function of the Lowe syndrome protein OCRL1.
    Traffic. 2005 Sep;6(9):711-9 PMID: 16101675
  20. Complementation analysis in PtdInsP kinase-deficient yeast mutants demonstrates that Schizosaccharomyces pombe and murine Fab1p homologues are phosphatidylinositol 3-phosphate 5-kinases.
    J Biol Chem. 1999 Nov 26;274(48):33905-12 PMID: 10567352
  21. Impaired PtdIns(4,5)P2 synthesis in nerve terminals produces defects in synaptic vesicle trafficking.
    Nature. 2004 Sep 23;431(7007):415-22 PMID: 15386003
  22. Regulation of Fab1 phosphatidylinositol 3-phosphate 5-kinase pathway by Vac7 protein and Fig4, a polyphosphoinositide phosphatase family member.
    Mol Biol Cell. 2002 Apr;13(4):1238-51 PMID: 11950935
  23. Essential role of phosphoinositide metabolism in synaptic vesicle recycling.
    Cell. 1999 Oct 15;99(2):179-88 PMID: 10535736
  24. Fab1 phosphatidylinositol 3-phosphate 5-kinase controls trafficking but not silencing of endocytosed receptors.
    Mol Biol Cell. 2006 Sep;17(9):3989-4001 PMID: 16837550
  25. The mammalian phosphatidylinositol 3-phosphate 5-kinase (PIKfyve) regulates endosome-to-TGN retrograde transport.
    J Cell Sci. 2006 Oct 1;119(Pt 19):3944-57 PMID: 16954148
  26. Creating new fluorescent probes for cell biology.
    Nat Rev Mol Cell Biol. 2002 Dec;3(12):906-18 PMID: 12461557
  27. Reducing the environmental sensitivity of yellow fluorescent protein. Mechanism and applications.
    J Biol Chem. 2001 Aug 3;276(31):29188-94 PMID: 11387331
  28. Vacuole size control: regulation of PtdIns(3,5)P2 levels by the vacuole-associated Vac14-Fig4 complex, a PtdIns(3,5)P2-specific phosphatase.
    Mol Biol Cell. 2004 Jan;15(1):24-36 PMID: 14528018
  29. Characterization of MTMR3. an inositol lipid 3-phosphatase with novel substrate specificity.
    Curr Biol. 2001 Oct 16;11(20):1600-5 PMID: 11676921
  30. Phosphatidylinositol-5-phosphate activation and conserved substrate specificity of the myotubularin phosphatidylinositol 3-phosphatases.
    Curr Biol. 2003 Mar 18;13(6):504-9 PMID: 12646134
  31. A new pathway for synthesis of phosphatidylinositol-4,5-bisphosphate.
    Nature. 1997 Nov 13;390(6656):192-6 PMID: 9367159
  32. Vac14 controls PtdIns(3,5)P(2) synthesis and Fab1-dependent protein trafficking to the multivesicular body.
    Curr Biol. 2002 Jun 4;12(11):885-93 PMID: 12062051
  33. Phosphoinositide signaling disorders in human diseases.
    FEBS Lett. 2003 Jul 3;546(1):25-31 PMID: 12829232
  34. Phosphatidylinositol 5-phosphate biosynthesis is linked to PIKfyve and is involved in osmotic response pathway in mammalian cells.
    J Biol Chem. 2002 Dec 6;277(49):47276-84 PMID: 12270933
  35. A mammalian ortholog of Saccharomyces cerevisiae Vac14 that associates with and up-regulates PIKfyve phosphoinositide 5-kinase activity.
    Mol Cell Biol. 2004 Dec;24(23):10437-47 PMID: 15542851
  36. The Vac14p-Fig4p complex acts independently of Vac7p and couples PI3,5P2 synthesis and turnover.
    J Cell Biol. 2006 Feb 27;172(5):693-704 PMID: 16492811
  37. A null mutation in inositol polyphosphate 4-phosphatase type I causes selective neuronal loss in weeble mutant mice.
    Neuron. 2001 Oct 25;32(2):203-12 PMID: 11683991
  38. Phosphatidylinositol 3,5-bisphosphate defines a novel PI 3-kinase pathway in resting mouse fibroblasts.
    Biochem J. 1997 May 1;323 ( Pt 3):597-601 PMID: 9169590
  39. Fab1p PtdIns(3)P 5-kinase function essential for protein sorting in the multivesicular body.
    Cell. 1998 Dec 11;95(6):847-58 PMID: 9865702
  40. Type I phosphatidylinositol-4-phosphate 5-kinases synthesize the novel lipids phosphatidylinositol 3,5-bisphosphate and phosphatidylinositol 5-phosphate.
    J Biol Chem. 1998 Jul 17;273(29):18040-6 PMID: 9660759
  41. PtdIns(3,5)P2 is required for delivery of endocytic cargo into the multivesicular body.
    Traffic. 2003 Jul;4(7):479-90 PMID: 12795693
  42. Retrograde transport from endosomes to the trans-Golgi network.
    Nat Rev Mol Cell Biol. 2006 Aug;7(8):568-79 PMID: 16936697
  43. Model-guided microarray implicates the retromer complex in Alzheimer's disease.
    Ann Neurol. 2005 Dec;58(6):909-19 PMID: 16315276
  44. The phosphoinositide kinase PIKfyve/Fab1p regulates terminal lysosome maturation in Caenorhabditis elegans.
    Mol Biol Cell. 2006 Jul;17(7):3062-74 PMID: 16801682
  45. Gene silencing reveals a specific function of hVps34 phosphatidylinositol 3-kinase in late versus early endosomes.
    J Cell Sci. 2006 Apr 1;119(Pt 7):1219-32 PMID: 16522686
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0702275104
Published
2007-10-30
Epub
2007-00-23
Pages
17518-23
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2077288
Subset
IM
Grants
NIDDK NIH HHS · P50 DK052617 · United States
NIDDK NIH HHS · P50 DK52617 · United States
NIGMS NIH HHS · T32 GM07544 · United States
NIGMS NIH HHS · R01 GM024872 · United States
NIGMS NIH HHS · T32 GM007544 · United States
NIGMS NIH HHS · R01 GM050403 · United States
NIGMS NIH HHS · R01 GM24872 · United States
NINDS NIH HHS · R01 NS064015 · United States
NIGMS NIH HHS · R01 GM50403 · United States
External Links
PubMed source DOI: 10.1073/pnas.0702275104 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2