title: Olfactory stem cells, a new cellular model for studying molecular mechanisms underlying familial dysautonomia.
abstract: BACKGROUND
  Familial dysautonomia (FD) is a hereditary neuropathy caused by mutations in the IKBKAP gene, the most common of which results in variable tissue-specific mRNA splicing with skipping of exon 20. Defective splicing is especially severe in nervous tissue, leading to incomplete development and progressive degeneration of sensory and autonomic neurons. The specificity of neuron loss in FD is poorly understood due to the lack of an appropriate model system. To better understand and modelize the molecular mechanisms of IKBKAP mRNA splicing, we collected human olfactory ecto-mesenchymal stem cells (hOE-MSC) from FD patients. hOE-MSCs have a pluripotent ability to differentiate into various cell lineages, including neurons and glial cells.
  
  
  RESULTS
  We confirmed IKBKAP mRNA alternative splicing in FD hOE-MSCs and identified 2 novel spliced isoforms also present in control cells. We observed a significant lower expression of both IKBKAP transcript and IKAP/hELP1 protein in FD cells resulting from the degradation of the transcript isoform skipping exon 20. We localized IKAP/hELP1 in different cell compartments, including the nucleus, which supports multiple roles for that protein. We also investigated cellular pathways altered in FD, at the genome-wide level, and confirmed that cell migration and cytoskeleton reorganization were among the processes altered in FD. Indeed, FD hOE-MSCs exhibit impaired migration compared to control cells. Moreover, we showed that kinetin improved exon 20 inclusion and restores a normal level of IKAP/hELP1 in FD hOE-MSCs. Furthermore, we were able to modify the IKBKAP splicing ratio in FD hOE-MSCs, increasing or reducing the WT (exon 20 inclusion):MU (exon 20 skipping) ratio respectively, either by producing free-floating spheres, or by inducing cells into neural differentiation.
  
  
  CONCLUSIONS
  hOE-MSCs isolated from FD patients represent a new approach for modeling FD to better understand genetic expression and possible therapeutic approaches. This model could also be applied to other neurological genetic diseases.
authors.affiliation: NICN-CNRS UMR 6184, Université de la Méditerranée-Faculté de Médecine Nord, IFR Jean Roche, Marseille, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boone
authors.forename: Béatrice
authors.initials: B
authors.lastname: Loriod
authors.forename: Aurélie
authors.initials: A
authors.lastname: Bergon
authors.forename: Oualid
authors.initials: O
authors.lastname: Sbai
authors.forename: Christine
authors.initials: C
authors.lastname: Formisano-Tréziny
authors.forename: Jean
authors.initials: J
authors.lastname: Gabert
authors.forename: Michel
authors.initials: M
authors.lastname: Khrestchatisky
authors.forename: Catherine
authors.initials: C
authors.lastname: Nguyen
authors.forename: François
authors.initials: F
authors.lastname: Féron
authors.forename: Felicia B
authors.initials: FB
authors.lastname: Axelrod
authors.forename: El Chérif
authors.initials: EC
authors.lastname: Ibrahim
mesh_terms: D017398:Alternative Splicing; D001341:Autonomic Nervous System; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D004402:Dysautonomia, Familial / Q000378:metabolism*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology; D009457:Neuroglia / Q000166:cytology; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D020033:Protein Isoforms; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism; D012903:Smell / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology*
chemical_list: D020033:Protein Isoforms; D012333:RNA, Messenger