The inactivation of the Hnf1β gene identified an essential role in epithelial differentiation of the visceral endoderm

Liver organogenesis starts around day 10 of mouse embryonic development and is completed after birth. This process requires the simultaneous differentiation of several cell types, including hepatocytes and biliary epithelial cells (BEC), and the formation of precise three-dimensional structures. Several groups have attempted to unravel the genetic program that controls hepatocytes and BEC differentiation by characterizing transcription factors enriched in these cells (Cereghini, 1996). Among these factors, the homeoprotein HNF1β/vHNF1 (hepatocyte nuclear factor 1β or variant hepatocyte nuclear factor 1) presents an interesting expression pattern. It is detectable in the hepatic bud and is abundantly expressed in the gallbladder primordium (Coffinier et al., 1999a). It is detected later in the intrahepatic bile ducts (IHBD) as they develop within the liver. At the adult stage, HNF1β is strongly expressed throughout the biliary system. It is also expressed in periportal hepatocytes. This expression pattern distinguishes HNF1β from the closely related HNF1α protein that is uniformly distributed in all hepatocytes, and is expressed at lower levels in BEC (Pontoglio et al., 1996). The difference in expression of the two genes is interesting in light of the liver zonation phenomenon (Jungermann and Katz, 1982). Hepatocyte activities are specialized along the porto-central axis; catabolic metabolism occurs in the periportal hepatocytes, whereas anabolic functions are performed by hepatocytes closer to the central vein. Thus, the balance between the two HNF1 activities along the lobules may determine which hepatic genes are activated at a given position. In addition to its hepatic expression, Hnf1β (Tcf2 – Mouse Genome Informatics) is strongly expressed in several epithelia organized in tubules, such as the pancreatic exocrine ducts and the kidney tubules (De Simone et al., 1991; Lazzaro et al., 1992). As HNF1β is expressed from the very onset of formation of such structures, it might play a role during differentiation and organogenesis (Coffinier et al., 1999a; Ott et al., 1991). Furthermore, gene inactivation demonstrated an early requirement for Hnf1β in the differentiation of another epithelium, the visceral endoderm (Barbacci et al., 1999; Coffinier et al., 1999b). HNF1β mutation blocks the differentiation of visceral endoderm and prevents its specialization into the two cell types that are specific for the embryonic and extra-embryonic territories. As visceral endoderm fails to differentiate, HNF1β-null mice die around the time of gastrulation, preventing further study of the role of HNF1β during later differentiation events. 1829 Development 129, 1829-1838 (2002) Printed in Great Britain © The Company of Biologists Limited 2002 DEV2839