Intrahepatic Bile Ducts Develop According to a New Mode of Tubulogenesis Regulated by the Transcription Factor SOX9

Abstract

BACKGROUND AND AIMS-A number of diseases are characterized by defective formation of the intrahepatic bile ducts. In the embryo, hepatoblasts differentiate to cholangiocytes which give rise to the intrahepatic bile ducts. Here we investigated how these ducts develop in mouse liver and characterized the role of the transcription factor SOX9.

Sry HMG Box Protein 9-positive (Sox9+) Epithelial Cell Adhesion Molecule-negative (EpCAM−) Biphenotypic Cells Derived from Hepatocytes Are Involved in Mouse Liver Regeneration

“…We compared expression of Grhl2, and Sox9 as well as HNF1␤ in the liver of DDC-fed mice with that in the normal liver. Consistent with previous studies (23,25), HNF1␤, Grhl2, and Sox9 were detected in the nuclei of EpCAM ϩ bile duct cells in the normal liver (Fig. 1B, contrast, Sox9 was obviously expressed in cells other than EpCAM ϩ ductular cells (Fig.…”

In vivo reprogramming of Sox9 + cells in the liver to insulin-secreting ducts

“…Moreover the experiments with the Sox9-CreER; mTmG mice show that they arise from cells labeled for Sox9 expression at the ductal plate stage of development. These are probably small bile ducts (22,23) but the cells of origin might also be hepatoblastlike progenitor cells, thought to be in the periportal region associated with small bile ducts (26,27) or perhaps they derive from the peribiliary glands, which are associated with larger bile ducts and are reported to contain cells expressing markers characteristic of embryonic endoderm (18,19,(28)(29)(30)(31)(32).…”

“…These arise in the second half of gestation from structures called ductal plates, which form around the portal veins (17). The Sox9 gene is expressed in early cells of the ductal plates and its expression persists in small but not large bile ducts after birth (18,19).…”

MiniSOX9, a dominant-negative variant in colon cancer cells

“…Heterozygous mutations of the SOX9 gene are responsible for campomelic dysplasia (Foster et al, 1994), an autosomal dominant disorder resulting in skeletal and developmental abnormalities and in frequent neonatal death because of respiratory deficiencies (Houston et al, 1983). SOX9 was then shown to be a key regulator of chondrogenesis (Akiyama et al, 2002), neurogenesis (Stolt et al, 2003), male sex determination (Chaboissier et al, 2004), neural crest development (Cheung et al, 2005) and biliary development (Antoniou et al, 2009). SOX9 is overexpressed in tumors from many origins and particularly in colon (Blache et al, 2004;Jay et al, 2005), but its role in cancer appears mostly antioncogenic.…”