Prox1 ablation in hepatic progenitors causes defective hepatocyte specification and increases biliary cell commitment

Asha Seth, Jianming Ye, Nanjia Yu, Fanny Guez, David C. Bedford, Geoffrey A. Neale, Sabine Cordi, Paul K. Brindle, Frederic P. Lemaigre, Klaus H. Kaestner, Beatriz Sosa-Pineda*

*Corresponding author for this work

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)538-547
Number of pages10
JournalDevelopment (Cambridge)
Volume141
Issue number3
DOIs
StatePublished - Jan 2014

Keywords

  • Hepatic precursors
  • Liver
  • Mouse
  • Prox1
  • TGFβ

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

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    Seth, A., Ye, J., Yu, N., Guez, F., Bedford, D. C., Neale, G. A., Cordi, S., Brindle, P. K., Lemaigre, F. P., Kaestner, K. H., & Sosa-Pineda, B. (2014). Prox1 ablation in hepatic progenitors causes defective hepatocyte specification and increases biliary cell commitment. Development (Cambridge), 141(3), 538-547. https://doi.org/10.1242/dev.099481