The zebrafish onecut gene hnf-6 functions in an evolutionarily conserved genetic pathway that regulates vertebrate biliary development.
Targeted disruption of the onecut transcription factor, hnf-6, alters mammalian biliary system development. We have identified a related zebrafish cDNA expressed in the developing liver that is a functional ortholog of mammalian hnf-6. Antisense-mediated knockdown of zebrafish hnf-6 perturbs development of the intrahepatic biliary system. Knockdown of zebrafish hnf-6 alters expression of vhnf1 and the zebrafish orthologs of other mammalian genes regulated by hnf-6. Coinjection of mRNA encoding zebrafish vhnf1 rescues the biliary phenotype of hnf-6 morphants. These experiments strongly suggest that hnf-6 and vhnf1 function within an evolutionarily conserved pathway that regulates biliary development. Forced expression of either hnf-6 or vhnf1 also produces biliary phenotypes. Altered bile duct development in both loss- and gain-of-function experiments suggests that zebrafish biliary cells are sensitive to the dosage of hnf-6-mediated gene transcription.
Matthews
Randolph P
RP
Division of Gastroenterology and Nutrition, Children's Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania School of Medicine, 19104, USA.
Lorent
Kristin
K
Russo
Pierre
P
Pack
Michael
M
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001652:Bile Ducts / Q000196:embryology / Q000648:ultrastructure; D005075:Biological Evolution; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D051539:Hepatocyte Nuclear Factor 1-beta; D051559:Hepatocyte Nuclear Factor 6; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D017403:In Situ Hybridization; D050356:Lipid Metabolism; D008099:Liver / Q000196:embryology* / Q000378:metabolism / Q000502:physiology / Q000648:ultrastructure; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism; D010179:Pancreas / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D016415:Sequence Alignment; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000033:anatomy & histology / Q000196:embryology* / Q000235:genetics / Q000502:physiology; D029961:Zebrafish Proteins
D004268:DNA-Binding Proteins; C496495:HNF1B protein, human; D051559:Hepatocyte Nuclear Factor 6; D018398:Homeodomain Proteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; D029961:Zebrafish Proteins; C496498:hnf1ba protein, zebrafish; D051539:Hepatocyte Nuclear Factor 1-beta