Hepatocyte nuclear factor 4alpha is essential for embryonic development of the mouse colon.
OBJECTIVE
Hepatocyte nuclear factor 4 alpha (HNF4alpha) 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 HNF4alpha 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 HNF4alpha on colon development.


RESULTS
Embryos were recovered at E18.5 that lacked HNF4alpha in their colons. Although early stages of colonic development occurred, HNF4alpha-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 HNF4alpha contained HNF4alpha-binding sites within putative transcriptional regulatory regions and a subset of these sites were occupied by HNF4alpha in vivo.


CONCLUSIONS
HNF4alpha 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.
Garrison
Wendy D
WD
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53326, USA.
Battle
Michele A
MA
Yang
Chuhu
C
Kaestner
Klaus H
KH
Sladek
Frances M
FM
Duncan
Stephen A
SA
D000818:Animals; D002452:Cell Count; D003106:Colon / Q000196:embryology*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D047108:Embryonic Development / Q000502:physiology; D005753:Gastric Mucosa / Q000196:embryology; D015870:Gene Expression / Q000502:physiology; D020397:Goblet Cells / Q000502:physiology; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000196:embryology; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction
D051557:Hepatocyte Nuclear Factor 4