De Jong-Curtain, TA and Parslow, AC and Trotter, AJ and Hall, NE and Verkade, H and Tabone, T and Christie, EL and Crowhurst, MO and Layton, JE and Shepherd, IT and Nixon, SJ and Parton, RG and Zon, LI and Stainier, DYR and Lieschke, GJ and Heath, JK, Abnormal nuclear pore formation triggers apoptosis in the intestinal epithelium of elys-deficient zebrafish, Gastroenterology, 136, (3) pp. 902-911. ISSN 0016-5085 (2009) [Refereed Article]
© 2009 by the AGA Institute
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.
|Item Type:||Refereed Article|
|Keywords:||zebrafish, elys, nuclear pore, apoptosis, intestinal epithelium, intestinal abnormalities|
|Research Division:||Biological Sciences|
|Research Group:||Biochemistry and Cell Biology|
|Research Field:||Cell Development, Proliferation and Death|
|Objective Group:||Clinical Health (Organs, Diseases and Abnormal Conditions)|
|Objective Field:||Cancer and Related Disorders|
|Author:||Trotter, AJ (Dr Andrew Trotter)|
|Web of Science® Times Cited:||27|
|Deposited By:||IMAS - Directorate|
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