ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2011
Congenital CNS hypomyelination in the Fig4 null mouse is rescued by neuronal expression of the PI(3,5)P(2) phosphatase Fig4.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 49 citations in OpenAlex.
- Deletion of murineScience translational medicine · 2025Article
- Clinical Characteristics of Charcot-Marie-Tooth Disease Type 4J.Neurology · 2024Article
- Chloroquine corrects enlarged lysosomes in FIG4 null cells and reduces neurodegeneration in Fig4 null mice.Molecular genetics and metabolism · 2022Article
- Review
- AAV9-mediated FIG4 delivery prolongs life span in Charcot-Marie-Tooth disease type 4J mouse model.The Journal of clinical investigation · 2021Article
- Intra-axonal mechanisms driving axon regeneration.Brain research · 2020Review
- Cerebral hypomyelination associated with biallelic variants of FIG4.Human mutation · 2019Article
- Protective role of the lipid phosphatase Fig4 in the adult nervous system.Human molecular genetics · 2018Article
- Article
- The DYT6 Dystonia Protein THAP1 Regulates Myelination within the Oligodendrocyte Lineage.Developmental cell · 2017Article
- Preferential conduction block of myelinated axons by nitric oxide.Journal of neuroscience research · 2017Article
- Transient auditory nerve demyelination as a new mechanism for hidden hearing loss.Nature communications · 2017Article
- PI(3,5)P2 biosynthesis regulates oligodendrocyte differentiation by intrinsic and extrinsic mechanisms.eLife · 2016Article
- Rescue of neurodegeneration in the Fig4 null mouse by a catalytically inactive FIG4 transgene.Human molecular genetics · 2016Article
- Th Cell Diversity in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis.Journal of immunology (Baltimore, Md. : 1950) · 2015Article
- Loss of PIKfyve in platelets causes a lysosomal disease leading to inflammation and thrombosis in mice.Nature communications · 2014Article
- Mouse models of PI(3,5)P2 deficiency with impaired lysosome function.Methods in enzymology · 2014Article
- Phosphatidylinositol 3,5-bisphosphate: low abundance, high significance.BioEssays : news and reviews in molecular, cellular and developmental biology · 2014Review
- Murine Fig4 is dispensable for muscle development but required for muscle function.Skeletal muscle · 2013Article
- The Sac domain-containing phosphoinositide phosphatases: structure, function, and disease.Frontiers in biology · 2013Article
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
The plt (pale tremor) mouse carries a null mutation in the Fig4(Sac3) gene that results in tremor, hypopigmentation, spongiform degeneration of the brain, and juvenile lethality. FIG4 is a ubiquitously expressed phosphatidylinositol 3,5-bisphosphate phosphatase that regulates intracellular vesicle trafficking along the endosomal-lysosomal pathway. In humans, the missense mutation FIG4(I41T) combined with a FIG4 null allele causes Charcot-Marie-Tooth 4J disease, a severe form of peripheral neuropathy. Here we show that Fig4 null mice exhibit a dramatic reduction of myelin in the brain and spinal cord. In the optic nerve, smaller-caliber axons lack myelin sheaths entirely, whereas many large- and intermediate-caliber axons are myelinated but show structural defects at nodes of Ranvier, leading to delayed propagation of action potentials. In the Fig4 null brain and optic nerve, oligodendrocyte (OL) progenitor cells are present at normal abundance and distribution, but the number of myelinating OLs is greatly compromised. The total number of axons in the Fig4 null optic nerve is not reduced. Developmental studies reveal incomplete myelination rather than elevated cell death in the OL linage. Strikingly, there is rescue of CNS myelination and tremor in transgenic mice with neuron-specific expression of Fig4, demonstrating a non-cell-autonomous function of Fig4 in OL maturation and myelin development. In transgenic mice with global overexpression of the human pathogenic FIG4 variant I41T, there is rescue of the myelination defect, suggesting that the CNS of CMT4J patients may be protected from myelin deficiency by expression of the FIG4(I41T) mutant protein.
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