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Abnormal nuclear pore formation triggers apoptosis in the intestinal epithelium of elys-deficient zebrafish

journal contribution
posted on 2023-05-19, 07:47 authored by De Jong-Curtain, TA, Parslow, AC, Andrew TrotterAndrew Trotter, Hall, NE, Verkade, H, Tabone, T, Christie, EL, Crowhurst, MO, Layton, JE, Shepherd, IT, Nixon, SJ, Parton, RG, Zon, LI, Stainier, DYR, Lieschke, GJ, Heath, JK

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.

History

Publication title

Gastroenterology

Volume

136

Pagination

902-911

ISSN

0016-5085

Department/School

Institute for Marine and Antarctic Studies

Publisher

W B Saunders Co

Place of publication

Independence Square West Curtis Center, Ste 300, Philadelphia, USA, Pa, 19106-3399

Rights statement

© 2009 by the AGA Institute

Repository Status

  • Restricted

Socio-economic Objectives

Clinical health not elsewhere classified

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