Hepatocyte nuclear factor 4α is essential for embryonic development of the mouse colon

Background & Aims: Hepatocyte nuclear factor 4 alpha (HNF4 alpha) is a transcription factor that has been shown to be required for hepatocyte differentiation and development of the liver. It has also been implicated in regulating expression of genes that act in the epithelium of the lower gastrointestinal tract. This implied that HNF4 alpha might be required for development of the gut. Methods: Mouse embryos were generated in which Hnf4a was ablated in the epithelial cells of the fetal colon by using Cre-loxP technology. Embryos were examined by using a combination of histology, immunohistochemistry, DNA microarray, reverse-transcription polymerase chain reaction, electrophoretic mobility shift assays, and chromatin immunoprecipitation analyses to define the consequences of loss of HNF4 alpha on colon development. Results: Embryos were recovered at E18.5 that lacked HNF4 alpha in their colons. Although early stages of colonic development occurred, HNF4 alpha-null colons failed to form normal crypts. In addition, goblet-cell maturation was perturbed and expression of an array of genes that encode proteins with diverse roles in colon function was disrupted. Several genes whose expression in the colon was dependent on HNF4 alpha contained HNF4 alpha-binding sites within putative transcriptional regulatory regions and a subset of these sites were occupied by HNF4 alpha in vivo. Conclusions: HNF4 alpha is a transcription factor that is essential for development of the mammalian colon, regulates goblet-cell maturation, and is required for expression of genes that control normal colon function and epithelial cell differentiation.