title: 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.
abstract: 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.
authors.affiliation: 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.
authors.forename: Sharon
authors.initials: S
authors.lastname: Lefler
authors.affiliation: The Hadassah Human Embryonic Stem Cell Research Center, The Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Ein Kerem, Jerusalem, Israel.
authors.forename: Malkiel A
authors.initials: MA
authors.lastname: Cohen
authors.affiliation: 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.
authors.forename: Gal
authors.initials: G
authors.lastname: Kantor
authors.affiliation: Department of Developmental Biology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Cheishvili
authors.affiliation: 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.
authors.forename: Aviel
authors.initials: A
authors.lastname: Even
authors.affiliation: The Hadassah Human Embryonic Stem Cell Research Center, The Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Ein Kerem, Jerusalem, Israel.
authors.forename: Anastasya
authors.initials: A
authors.lastname: Birger
authors.affiliation: The Hadassah Human Embryonic Stem Cell Research Center, The Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Ein Kerem, Jerusalem, Israel.
authors.forename: Tikva
authors.initials: T
authors.lastname: Turetsky
authors.affiliation: The Hadassah Human Embryonic Stem Cell Research Center, The Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Ein Kerem, Jerusalem, Israel.
authors.forename: Yaniv
authors.initials: Y
authors.lastname: Gil
authors.affiliation: The Hadassah Human Embryonic Stem Cell Research Center, The Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Ein Kerem, Jerusalem, Israel.
authors.forename: Sharona
authors.initials: S
authors.lastname: Even-Ram
authors.affiliation: Department of Obstetrics and Gynecology, Hadassah Hebrew University Medical Center, Ein Kerem, Jerusalem, Israel.
authors.forename: Einat
authors.initials: E
authors.lastname: Aizenman
authors.affiliation: Department of Obstetric and Gynecology, Hadassah Hospital Mount Scopus, Hebrew University Medical School, Jerusalem, Israel.
authors.forename: Nibal
authors.initials: N
authors.lastname: Bashir
authors.affiliation: Department of Pediatrics, Hadassah Hospital Mount Scopus, Hebrew University Medical School, Jerusalem, Israel.
authors.forename: Channa
authors.initials: C
authors.lastname: Maayan
authors.affiliation: Department of Developmental Biology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel.
authors.forename: Aharon
authors.initials: A
authors.lastname: Razin
authors.affiliation: 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.
authors.forename: Benjamim E
authors.initials: BE
authors.lastname: Reubinoff
authors.affiliation: 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.
authors.forename: Miguel
authors.initials: M
authors.lastname: Weil
mesh_terms: D001692:Biological Transport / Q000187:drug effects / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004402:Dysautonomia, Familial / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005333:Fetus; D000066449:Human Embryonic Stem Cells / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D007701:Kinetin / Q000494:pharmacology; D008297:Male; D009154:Mutation; D009432:Neural Crest / Q000187:drug effects / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D017933:Peripheral Nervous System / Q000187:drug effects / Q000473:pathology*; D010641:Phenotype; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism*; D035602:Transcriptional Elongation Factors
chemical_list: D002352:Carrier Proteins; C114720:Elp1 protein, human; D035602:Transcriptional Elongation Factors; D007701:Kinetin