yippee like 3 (ypel3) is a novel gene required for myelinating and perineurial glia development

作者：Bernardo Blanco-Sánchez, Aurélie Clément, Sarah J. Stednitz, Jennifer Kyle, Judy Peirce, Marcie McFadden, Jeremy Wegner, Jennifer B. Phillips, Ellen F. Macnamara, Yan Huang, David R. Adams, Camilo Toro, William A. Gahl, May Christine V. Malicdan, Cynthia J. Tifft, Erika Zink, Kent Bloodsworth, Kelly G. Stratton, Undiagnosed Diseases Network, David M. Koeller, Thomas Metz, Philip Washbourne, Monte Westerfield · 发表于：PLoS Genetics · 年份：2020 · DOI：10.1371/journal.pgen.1008841 · 被引用次数：23 · 研究领域：Neurogenesis and neuroplasticity mechanisms、MicroRNA in disease regulation、Cancer-related molecular mechanisms research

Hypomyelination, a neurological condition characterized by decreased production of myelin sheets by glial cells, often has no known etiology. Elucidating the genetic causes of hypomyelination provides a better understanding of myelination, as well as means to diagnose, council, and treat patients. Here, we present evidence that YIPPEE LIKE 3 (YPEL3), a gene whose developmental role was previously unknown, is required for central and peripheral glial cell development. We identified a child with a constellation of clinical features including cerebral hypomyelination, abnormal peripheral nerve conduction, hypotonia, areflexia, and hypertrophic peripheral nerves. Exome and genome sequencing revealed a de novo mutation that creates a frameshift in the open reading frame of YPEL3, leading to an early stop codon. We used zebrafish as a model system to validate that YPEL3 mutations are causative of neuropathy. We found that ypel3 is expressed in the zebrafish central and peripheral nervous system. Using CRISPR/Cas9 technology, we created zebrafish mutants carrying a genomic lesion similar to that of the patient. Our analysis revealed that Ypel3 is required for development of oligodendrocyte precursor cells, timely exit of the perineurial glial precursors from the central nervous system (CNS), formation of the perineurium, and Schwann cell maturation. Consistent with these observations, zebrafish ypel3 mutants have metabolomic signatures characteristic of oligodendrocyte and Schwann c...