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

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.We are studying the mammalian homologues of a number of Drosophila melanogaster genes concerned with development or behavior, as part of a program aimed at identifying novel mammalian developmental and neurobiological genes. The D. melanogaster flightless I (fliI) gene (4,15,23,24,33) is required for cellularization of the syncytial blastoderm. With severe mutations in fliI, when the contribution of maternal product is eliminated, cellularization is only partial and gastrulation fails (35,44).

Flightless, secreted through a late endosome/lysosome pathway, binds LPS and dampens cytokine secretion

“…Many actin-binding proteins, including gelsolin family members, also have a role within the nucleus and Flii is no exception (Lee et al, 2004;Lee and Stallcup, 2006;Liu and Yin, 1998). Mice that lack other members of the gelsolin family are viable and fertile while the homozygous knockout of Flii in mice is embryonically lethal (Campbell et al, 2002). These results suggest other essential roles for Flii and its functions have now expanded well beyond the gelsolin-like actin remodelling and transcriptional regulator role found with other members of the family (Dai et al, 2009;Hayashi et al, 2010;Li et al, 2008;Wang et al, 2006).…”

Flightless I Homolog Negatively Modulates the TLR Pathway

“…Fliih expression is also essential for early embryonic development in mice (38). It has been suggested that Fliih links signaling proteins to cytoskeletons (31).…”

Nucleoredoxin Negatively Regulates Toll-like Receptor 4 Signaling via Recruitment of Flightless-I to Myeloid Differentiation Primary Response Gene (88)

“…It was subsequently discovered that Fli-I is conserved throughout species from nematodes to humans (10). Fli-I knock-out in mice leads to early embryonic lethality, indicating the vital importance of this molecule across species (11). Fli-I possesses a leucine-rich repeat in the N terminus and a gelsolin-like domain in the C terminus.…”