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Molecular and Cellular Biology, March 2002, p. 1488-1494, Vol. 22, No. 5
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.5.1488-1494.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Embryonic Lethality Caused by Apoptosis during Gastrulation in Mice Lacking the Gene of the ADP-Ribosylation Factor-Related Protein 1

Institute of Pharmacology,¹ Institute of Pathology,² Institute of Animal Research, Medical Faculty, Technical University of Aachen, D-52057 Aachen,³ Institute of Toxicology and Genetics, Forschungszentrum Karlsruhe, D-76021 Karlsruhe, Germany⁴

Received 4 October 2001/ Returned for modification 27 November 2001/ Accepted 6 December 2001

ADP-ribosylation factor (ARF)-related protein 1 (ARFRP1) is a membrane-associated GTPase with significant similarity to the family of ARFs. We have recently shown that ARFRP1 interacts with the Sec7 domain of the ARF-specific guanine nucleotide exchange factor Sec7-1/cytohesin and inhibits the ARF/Sec7-dependent activation of phospholipase D in a GTP-dependent manner. In order to further analyze the function of ARFRP1, we cloned the mouse Arfrp1 gene and generated Arfrp1 null-mutant mice by gene targeting in embryonic stem cells. Heterozygous Arfrp1 mutants developed normally, whereas homozygosity for the mutant allele led to embryonic lethality. Cultured homozygous Arfrp1 null-mutant blastocysts were indistinguishable from wild-type blastocysts. In vivo, they implanted and formed egg cylinder stage embryos that appeared normal until day 5. Between embryonic days 6 and 7, however, apoptotic cell death of epiblast cells occurred in the embryonic ectoderm during gastrulation, as was shown by histological analysis combined with terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling. Epiblast cells that would normally differentiate to mesodermal cells detached from the ectodermal cell layer and were dispersed into the proamniotic cavity. In contrast, the development of extraembryonic structures appeared unaffected. Our results demonstrate that ARFRP1 is necessary for early embryonic development during gastrulation.

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