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Author Notes:

Assoc. Prof. Joan K. Heath, Joint-Head, Colon Molecular and Cell Biology Laboratory, Ludwig Institute for Cancer Research, Post Office Royal Melbourne Hospital, Parkville, Victoria 3050, Australia, Tel: (+613) 9341 3155, Fax: (+613) 9341 3104, joan.heath@ludwig.edu.au.

The authors thank Annie Ng, Elke Ober, Holly Field and Michel Bagnat for the flos871 mutant; Val Feakes (histology); Stephen Wilson (eye histology); Michel Bagnat and Helen Foote (genome scans); Bastian Ackermann, Andrew Badrock, Rossana Chung, Stephen Cody, Rachel Hancock, Sebastian Markmiller, Cam Tu Nguyen, Dora McPhee, Elsbeth Richardson, Alt Zantema (technical expertise); Janna Taylor and Pierre Smith (graphics); and Matthias Ernst and Tony Burgess (comments on the manuscript).

The authors declare no conflicts of interest related to this work.

Subjects:

Research Funding:

This work was supported by NHMRC Australia project grants 280916 and 433614 (JKH); NHMRC Dora Lush (Biomedical) Scholarship (TADJ-C); NHMRC Howard Florey Centenary Fellowship (HV); Australian Research Council grant DP0346823 (GJL); and NIH grants DK 067285 (ITS), K058181 and DK060322 (DYRS).

Keywords:

  • Animals
  • Apoptosis
  • Cell Differentiation
  • Cell Lineage
  • Enteric Nervous System
  • Eye Abnormalities
  • Gene Expression Regulation, Developmental
  • Intestinal Mucosa
  • Intestines
  • Liver
  • Microscopy, Electron
  • Nuclear Pore
  • Nuclear Pore Complex Proteins
  • Pancreas
  • Phenotype
  • Zebrafish
  • Zebrafish Proteins

Abnormal Nuclear Pore Formation Triggers Apoptosis in the Intestinal Epithelium of elys-Deficient Zebrafish

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Journal Title:

Gastroenterology

Volume:

Volume 136, Number 3

Publisher:

, Pages 902-911

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Background & Aims: 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.

Copyright information:

© 2009 AGA Institute.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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