GKLF (gut-enriched Kruppel-like factor) is a zinc-finger transcription factor expressed in the endoderm of the gastrointestinal tract. GKLF mRNA is found in high levels in growth- arrested cells and is nearly undetectable in cells in the exponential phase of proliferation. GKLF appears to inhibit DNA synthesis in cell culture. Preliminary data shows that homozygous null mice for fkh6 (forkhead homolog 6), a winged-helix transcription factor, have decreased levels of GKLF mRNA in all gastro intestinal tract tissues studied. Homozygous null mice for fkh6 have a dramatic increase in proliferating cells resulting in elongated villi in the small intestine and an expanded epithelium in the stomach. While Fkh6 is expressed only in the mesoderm of the gastrointestinal tract, the phenotypic changes of Fkh6 knockout mice occur in the endoderm- derived epithelium. GKLF is a good candidate for a downstream target for the action of Fkh6 via a mesoderm to endoderm signaling pathway. The following specific aims will be pursued: 1) To investigate the function of the zinc-finger transcription factor GKLF in gastrointestinal proliferation and differentiation in vivo; 2) To investigate the possible role of GKLF as a major downstream target for Fkh6 in a mesoderm to endoderm signaling pathway.
