Familial Dysautonomia (FD) Human Embryonic Stem Cell Derived PNS Neurons Reveal that Synaptic Vesicular and Neuronal Transport Genes Are Directly or Indirectly Affected by IKBKAP Downregulation.
- Resource Type
- Academic Journal
- Authors
- Lefler S; Laboratory for Neurodegenerative Diseases and Personalized Medicine, Department of Cell Research and Immunology, The George S. Wise Faculty of Life Sciences, The Sagol School of Neurosciences, Tel Aviv University, Tel Aviv, Israel.; Cohen MA; The Hadassah Human Embryonic Stem Cell Research Center, The Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Ein Kerem, Jerusalem, Israel.; Kantor G; Laboratory for Neurodegenerative Diseases and Personalized Medicine, Department of Cell Research and Immunology, The George S. Wise Faculty of Life Sciences, The Sagol School of Neurosciences, Tel Aviv University, Tel Aviv, Israel.; Cheishvili D; Department of Developmental Biology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel.; Even A; Laboratory for Neurodegenerative Diseases and Personalized Medicine, Department of Cell Research and Immunology, The George S. Wise Faculty of Life Sciences, The Sagol School of Neurosciences, Tel Aviv University, Tel Aviv, Israel.; Birger A; The Hadassah Human Embryonic Stem Cell Research Center, The Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Ein Kerem, Jerusalem, Israel.; Turetsky T; The Hadassah Human Embryonic Stem Cell Research Center, The Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Ein Kerem, Jerusalem, Israel.; Gil Y; The Hadassah Human Embryonic Stem Cell Research Center, The Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Ein Kerem, Jerusalem, Israel.; Even-Ram S; The Hadassah Human Embryonic Stem Cell Research Center, The Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Ein Kerem, Jerusalem, Israel.; Aizenman E; Department of Obstetrics and Gynecology, Hadassah Hebrew University Medical Center, Ein Kerem, Jerusalem, Israel.; Bashir N; Department of Obstetric and Gynecology, Hadassah Hospital Mount Scopus, Hebrew University Medical School, Jerusalem, Israel.; Maayan C; Department of Pediatrics, Hadassah Hospital Mount Scopus, Hebrew University Medical School, Jerusalem, Israel.; Razin A; Department of Developmental Biology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel.; Reubinoff BE; The Hadassah Human Embryonic Stem Cell Research Center, The Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Ein Kerem, Jerusalem, Israel; Department of Obstetrics and Gynecology, Hadassah Hebrew University Medical Center, Ein Kerem, Jerusalem, Israel.; Weil M; Laboratory for Neurodegenerative Diseases and Personalized Medicine, Department of Cell Research and Immunology, The George S. Wise Faculty of Life Sciences, The Sagol School of Neurosciences, Tel Aviv University, Tel Aviv, Israel.
- Source
- Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE
- Subject
- Language
- English
A splicing mutation in the IKBKAP gene causes Familial Dysautonomia (FD), affecting the IKAP protein expression levels and proper development and function of the peripheral nervous system (PNS). Here we found new molecular insights for the IKAP role and the impact of the FD mutation in the human PNS lineage by using a novel and unique human embryonic stem cell (hESC) line homozygous to the FD mutation originated by pre implantation genetic diagnosis (PGD) analysis. We found that IKBKAP downregulation during PNS differentiation affects normal migration in FD-hESC derived neural crest cells (NCC) while at later stages the PNS neurons show reduced intracellular colocalization between vesicular proteins and IKAP. Comparative wide transcriptome analysis of FD and WT hESC-derived neurons together with the analysis of human brains from FD and WT 12 weeks old embryos and experimental validation of the results confirmed that synaptic vesicular and neuronal transport genes are directly or indirectly affected by IKBKAP downregulation in FD neurons. Moreover we show that kinetin (a drug that corrects IKBKAP alternative splicing) promotes the recovery of IKAP expression and these IKAP functional associated genes identified in the study. Altogether, these results support the view that IKAP might be a vesicular like protein that might be involved in neuronal transport in hESC derived PNS neurons. This function seems to be mostly affected in FD-hESC derived PNS neurons probably reflecting some PNS neuronal dysfunction observed in FD.