Abstract
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.