REGULATORY CASCADES IN GASTROINTESTINAL PROLIFERATION

University Of Pennsylvania, Philadelphia PA

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Abstract

GKLF (gut-enriched Kruppel-like factor) is a zinc-finger transcription factor expressed in the epithelium of the gastrointestinal tract. Previous studies demonstrate a vital role for GKLF in cell proliferation and/or differentiation. GKLF mRNA is found at high levels in growth-arrested cells and is nearly undetectable in cells undergoing proliferation. GKLF RNA localizes to the upper region of the colonic crypt epithelium, a region thought to consist of cells which have undergone growth arrest and begun to differentiate into mature colonocytes. GKLF expression is down- regulated in homozygous null mice for the mesenchymal transcription factor Fkh6 (forkhead homolog 6), an important model of perturbed gastrointestinal differentiation and proliferation. While Fkh6 is expressed exclusively in the mesenchyme of the gastrointestinal tract, the phenotypic consequences of Fkh6 ablation are the abnormal proliferation and differentiation of the gastrointestinal epithelium. GKLF is thus an excellent candidate for a major downstream target for the action of Fkh6 via a mesoderm to endoderm signaling pathway. We will explore the role of GKLF in the regulation of gastrointestinal proliferation and differentiation in vivo by testing the following hypotheses: (1) Mice lacking the transcription.factor GKLF will have severe perturbations in the control of proliferation in the gastrointestinal epithelium, (2) Mice lacking the transcription factor GKLF will have abnormal intestinal absorption due to disruption of normal differentiation and proliferation of the intestinal epithelium, and (3) GKLF is a major downstream target.for the action of the mesenchymal transcription factor Fkh6. The following specific aims will be pursued: (1) To analyze the function of GKLF in gastrointestinal development, cell growth, and differentiation by morphological analyses of homozygous null mutants and tissue-specific null mutants for the transcription factor GKLF, (2) To analyze the effects of GKLF on gastrointestinal physiology by studies of intestinal uptake in mice lacking the transcription factor GKLF in the gastrointestinal tract, and (3) To study the role of GKLF as a potential downstream target for the mesenchymal transcription factor Fkh6 in a mesodermal-endodermal signaling pathway by generating double mutants for Fkh6 and GKLF.