Mesodermal Wnt2b signalling positively regulates liver specification

Abstract

Endodermal organs such as the lung, liver and pancreas emerge at precise locations along the primitive gut tube. Although several signalling pathways have been implicated in liver formation, so far no single gene has been identified that exclusively regulates liver specification. In zebrafish, the onset of liver specification is marked by the localized endodermal expression of hhex and prox1 at 22 hours post fertilization. Here we used a screen for mutations affecting endodermal organ morphogenesis to identify a unique phenotype: prometheus (prt) mutants exhibit profound, though transient, defects in liver specification. Positional cloning reveals that prt encodes a previously unidentified Wnt2b homologue. prt/wnt2bb is expressed in restricted bilateral domains in the lateral plate mesoderm directly adjacent to the liver-forming endoderm. Mosaic analyses show the requirement for Prt/Wnt2bb in the lateral plate mesoderm, in agreement with the inductive properties of Wnt signalling. Taken together, these data reveal an unexpected positive role for Wnt signalling in liver specification, and indicate a possible common theme for the localized formation of endodermal organs along the gut tube.

Liver growth in the embryo and during liver regeneration in zebrafish requires the cell cycle regulator, uhrf1

“…In comparison to the advances in understanding of hepatic patterning (17,18,39), hepatic outgrowth is understudied. Mouse knockout models have revealed a handful of genes that are required for outgrowth and have demonstrated that disruption of a number of these genes results in hepatic hypoplasia and apoptosis (4,5,10,11,12,40).…”

hgf/c‐met expression and functional analysis during zebrafish embryogenesis

“…At this stage, wnt2bb and canonical Wnt signaling are required for hepatic specification (Ober et al, 2006). Transcripts for Wnt2bb are expressed in posterior lateral plate me-soderm from the onset of somitogenesis and appear bilaterally near the midline in the liver-forming region at 18 -21 hr (Ober et al, 2006).…”

Endodermal and mesenchymal cross talk: a crossroad for the maturation of foregut organs

“…Intriguingly, other homeobox genes have been implicated at similar timepoints in HE cells and result in similar defects. Both of the homeobox genes Hhex and Prox1 have been proposed to be involved in liver specification in zebrafish and mice and mutants show similar phenotypes (13,49,50). Prox1 is not known to be expressed in ECs and the failure of the HE cells to migrate in Prox1 −/− embryos may be dependent on its interaction with other HE genes (Hhex and Tbx3).…”

“…The regulation of the hepatocyte/BEC cell fate decision may be in part regulated (42,50), and the regulation of Hnf4α has also been implicated in multiple aspects of liver development (though it is not required for hepatic specification). Hnf4α may be critical to reinduce a proper epithelial morphology on the endodermal cells after migration through the STM and to reduce EMT by stimulating high levels of cell adhesion genes (33).…”