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Molecular and Cellular Biology, May 2002, p. 3518-3526, Vol. 22, No. 10
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.10.3518-3526.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Fliih, a Gelsolin-Related Cytoskeletal Regulator Essential for Early Mammalian Embryonic Development

Hugh D. Campbell,^1* Shelley Fountain,¹ Ian S. McLennan,^2,3 Leise A. Berven,² Michael F. Crouch,^2,4 Deborah A. Davy,² Jane A. Hooper,¹ Kynan Waterford,¹ Ken-Shiung Chen,⁵ James R. Lupski,⁵ Birgit Ledermann,⁶ Ian G. Young,⁷ and Klaus I. Matthaei⁷

Molecular Genetics and Evolution Group, Research School of Biological Sciences,¹ Division of Neurosciences,² Division of Biochemistry and Molecular Biology, John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601,⁷ GroPep Ltd., Thebarton, SA 5031, Australia,⁴ Department of Anatomy and Structural Biology, University of Otago, Dunedin, New Zealand,³ Department of Molecular and Human Genetics, Baylor College of Medicine, Texas Medical Center, Houston, Texas 77030-3498,⁵ Institut für Labortierkunde, Universität Zürich-Irchel, 8057 Zürich, Switzerland⁶

Received 29 October 2001/ Returned for modification 29 January 2002/ Accepted 18 February 2002

The Drosophila melanogaster flightless I gene is required for normal cellularization of the syncytial blastoderm. Highly conserved homologues of flightless I are present in Caenorhabditis elegans, mouse, and human. We have disrupted the mouse homologue Fliih by homologous recombination in embryonic stem cells. Heterozygous Fliih mutant mice develop normally, although the level of Fliih protein is reduced. Cultured homozygous Fliih mutant blastocysts hatch, attach, and form an outgrowing trophoblast cell layer, but egg cylinder formation fails and the embryos degenerate. Similarly, Fliih mutant embryos initiate implantation in vivo but then rapidly degenerate. We have constructed a transgenic mouse carrying the complete human FLII gene and shown that the FLII transgene is capable of rescuing the embryonic lethality of the homozygous targeted Fliih mutation. These results confirm the specific inactivation of the Fliih gene and establish that the human FLII gene and its gene product are functional in the mouse. The Fliih mouse mutant phenotype is much more severe than in the case of the related gelsolin family members gelsolin, villin, and CapG, where the homozygous mutant mice are viable and fertile but display alterations in cytoskeletal actin regulation.

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* Corresponding author. Mailing address: Molecular Genetics and Evolution Group, Research School of Biological Sciences, Australian National University, P.O. Box 475, Canberra, ACT 2601, Australia. Phone: 61-2-6125-5080. Fax: 61-2-6125-8294. E-mail: Hugh.Campbell{at}anu.edu.au.

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Molecular and Cellular Biology, May 2002, p. 3518-3526, Vol. 22, No. 10
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.10.3518-3526.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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