Prox1 ablation in hepatic progenitors causes defective hepatocyte specification and increases biliary cell commitment.
The liver has multiple functions that preserve homeostasis. Liver diseases are debilitating, costly and often result in death. Elucidating the developmental mechanisms that establish the liver's architecture or generate the cellular diversity of this organ should help advance the prevention, diagnosis and treatment of hepatic diseases. We previously reported that migration of early hepatic precursors away from the gut epithelium requires the activity of the homeobox gene Prox1. Here, we show that Prox1 is a novel regulator of cell differentiation and morphogenesis during hepatogenesis. Prox1 ablation in bipotent hepatoblasts dramatically reduced the expression of multiple hepatocyte genes and led to very defective hepatocyte morphogenesis. As a result, abnormal epithelial structures expressing hepatocyte and cholangiocyte markers or resembling ectopic bile ducts developed in the Prox1-deficient liver parenchyma. By contrast, excessive commitment of hepatoblasts into cholangiocytes, premature intrahepatic bile duct morphogenesis, and biliary hyperplasia occurred in periportal areas of Prox1-deficient livers. Together, these abnormalities indicate that Prox1 activity is necessary to correctly allocate cell fates in liver precursors. These results increase our understanding of differentiation anomalies in pathological conditions and will contribute to improving stem cell protocols in which differentiation is directed towards hepatocytes and cholangiocytes.
Department of Genetics, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Asha
A
Seth
Jianming
J
Ye
Nanjia
N
Yu
Fanny
F
Guez
David C
DC
Bedford
Geoffrey A
GA
Neale
Sabine
S
Cordi
Paul K
PK
Brindle
Frederic P
FP
Lemaigre
Klaus H
KH
Kaestner
Beatriz
B
Sosa-Pineda
D000375:Aging / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001652:Bile Ducts / Q000473:pathology*; D002452:Cell Count; D019070:Cell Lineage / Q000235:genetics; D002828:Choristoma / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005333:Fetus / Q000378:metabolism; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology*; D018398:Homeodomain Proteins / Q000378:metabolism; D008099:Liver / Q000196:embryology / Q000378:metabolism; D051379:Mice; D055758:SOX9 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000378:metabolism; D000098551:Prospero-Related Homeobox 1 Protein
D051557:Hepatocyte Nuclear Factor 4; C496593:Hnf4a protein, mouse; D018398:Homeodomain Proteins; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein
Hepatic precursors; Liver; Mouse; Prox1; TGFβ