title: Abnormal nuclear pore formation triggers apoptosis in the intestinal epithelium of elys-deficient zebrafish.
abstract: OBJECTIVE
  Zebrafish mutants generated by ethylnitrosourea-mutagenesis provide a powerful tool for dissecting the genetic regulation of developmental processes, including organogenesis. One zebrafish mutant, "flotte lotte" (flo), displays striking defects in intestinal, liver, pancreas, and eye formation at 78 hours postfertilization (hpf). In this study, we sought to identify the underlying mutated gene in flo and link the genetic lesion to its phenotype.
  
  
  METHODS
  Positional cloning was employed to map the flo mutation. Subcellular characterization of flo embryos was achieved using histology, immunocytochemistry, bromodeoxyuridine incorporation analysis, and confocal and electron microscopy.
  
  
  RESULTS
  The molecular lesion in flo is a nonsense mutation in the elys (embryonic large molecule derived from yolk sac) gene, which encodes a severely truncated protein lacking the Elys C-terminal AT-hook DNA binding domain. Recently, the human ELYS protein has been shown to play a critical, and hitherto unsuspected, role in nuclear pore assembly. Although elys messenger RNA (mRNA) is expressed broadly during early zebrafish development, widespread early defects in flo are circumvented by the persistence of maternally expressed elys mRNA until 24 hpf. From 72 hpf, elys mRNA expression is restricted to proliferating tissues, including the intestinal epithelium, pancreas, liver, and eye. Cells in these tissues display disrupted nuclear pore formation; ultimately, intestinal epithelial cells undergo apoptosis.
  
  
  CONCLUSIONS
  Our results demonstrate that Elys regulates digestive organ formation.
authors.affiliation: Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Tanya A
authors.initials: TA
authors.lastname: de Jong-Curtain
authors.forename: Adam C
authors.initials: AC
authors.lastname: Parslow
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Trotter
authors.forename: Nathan E
authors.initials: NE
authors.lastname: Hall
authors.forename: Heather
authors.initials: H
authors.lastname: Verkade
authors.forename: Tania
authors.initials: T
authors.lastname: Tabone
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Christie
authors.forename: Meredith O
authors.initials: MO
authors.lastname: Crowhurst
authors.forename: Judith E
authors.initials: JE
authors.lastname: Layton
authors.forename: Iain T
authors.initials: IT
authors.lastname: Shepherd
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Nixon
authors.forename: Robert G
authors.initials: RG
authors.lastname: Parton
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Zon
authors.forename: Didier Y R
authors.initials: DY
authors.lastname: Stainier
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Lieschke
authors.forename: Joan K
authors.initials: JK
authors.lastname: Heath
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage / Q000502:physiology; D017615:Enteric Nervous System / Q000002:abnormalities / Q000473:pathology / Q000502:physiology; D005124:Eye Abnormalities / Q000473:pathology / Q000503:physiopathology; D018507:Gene Expression Regulation, Developmental; D007413:Intestinal Mucosa / Q000002:abnormalities* / Q000473:pathology / Q000502:physiology*; D007422:Intestines / Q000002:abnormalities / Q000473:pathology / Q000502:physiology; D008099:Liver / Q000002:abnormalities / Q000473:pathology / Q000502:physiology; D008854:Microscopy, Electron; D022022:Nuclear Pore / Q000473:pathology* / Q000502:physiology / Q000648:ultrastructure; D028861:Nuclear Pore Complex Proteins / Q000235:genetics* / Q000378:metabolism; D010179:Pancreas / Q000002:abnormalities / Q000473:pathology / Q000502:physiology; D010641:Phenotype; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C533929:AHCTF1 protein, zebrafish; D028861:Nuclear Pore Complex Proteins; D029961:Zebrafish Proteins