Sox9 and programming of liver and pancreatic progenitors

Abstract

Recent advances in developmental biology have greatly expanded our understanding of progenitor cell programming and the fundamental roles that Sox9 plays in liver and pancreas organogenesis. In the last 2 years, several studies have dissected the behavior of the Sox9+ duct cells in adult organs, but conflicting results have left unanswered the long-standing question of whether physiologically functioning progenitors exist in adult liver and pancreas. On the other hand, increasing evidence suggests that duct cells function as progenitors in the tissue restoration process after injury, during which embryonic programs are sometimes reactivated. This article discusses the role of Sox9 in programming liver and pancreatic progenitors as well as controversies in the field.

Figure 1. Tamoxifen-inducible Cre-mediated lineage tracing.

Cre recombinase is fused with the ligand-binding domain of the estrogen receptor. Tamoxifen administration enables the CreER fusion protein to enter the nucleus then excise the STOP cassette of ROSA26r, resulting in permanent labeling of the progeny. Such strategies have been instrumental to understanding the role of Sox9 in pancreatic and liver progenitor cells.

Figure 2. Maintenance of pancreatic fate and gene regulation in the programming of pancreatic endocrine progenitors.

A Fgf10/Fgfr2b/Sox9 feed-forward loop functions in the maintenance of pancreatic fate and expansion of early pancreatic precursors. Sox9 promotes the expression of Fgfr2b, which transduces signaling from Fgf10. Moreover, Fgf10 signaling promotes the expression of Fgfr2b and Sox9 in pancreatic progenitors. In the endocrine differentiation, a parallel regulatory circuitry exists, involving Notch, Hes1, Sox9, and Ngn3 (–33).

Figure 3. The continuous Sox9-expressing domain in adults.

Sox9 expression is detected throughout the pancreatic ducts, intra- and extrahepatic ducts, and in the intestinal crypt connected through the papilla of Vater, forming a contiguous Sox9⁺ zone.