DepartmentPattern Formation
Publication date26-July-2007

Norifumi Tatsumi, Rika Miki, Kenjiro Katsu, and Yuji Yokouchi (2007) Neurturin-GFRα2 signaling controls liver bud migration along the ductus venosus in the chick embryo. Developmental Biology, 307, 14–28.

  During chick liver development, the liver bud arises from the foregut, invaginates into the septum transversum, and elongates along and envelops the ductus venosus. However, the mechanism of liver bud migration is only poorly understood. Here, we demonstrate that a GDNF-family ligand involved in neuronal outgrowth and migration, neurturin (NRTN), and its receptor, GFRα2, are essential for liver bud migration. In the chick embryo, we found that GFRα2 was expressed in the liver bud and that NRTN was expressed in the endothelial cells of the ductus venosus. Inhibition of GFRα2 signaling suppressed liver bud elongation along the ductus venous without affecting cell proliferation and apoptosis. Moreover, ectopic expression of NRTN perturbed the directional migration along the ductus venosus, leading to splitting or ectopic branching of the liver. We showed that liver buds selectively migrated toward an NRTN-soaked bead in vitro . These data represent a new model for liver bud migration: NRTN secreted from endothelial cells functions as a chemoattractant to direct the migration of the GFRα2-expressing liver bud in early liver development.



Figure. (A-F) Expression of GFRα2-Fc inhibits liver bud elongation along the ductus venosus. The gross morphology of the liver bud (HH17) and liver (HH22) expressing pCAGGS as a control (A, D), pCAGGS- GFR a 2-Fc (B, E) and pCAGGS- GFRα1-Fc (C, F). After culture for 24 h (A-C) or 48 h (D-F), the hepatic epithelium of the liver bud or the liver was visualized by whole-mount in situ hybridization to an hhex probe. Arrowheads show the liver buds. Note that liver bud elongation was inhibited by expression of GFRα2-Fc (B, E). The orientation of the embryos are indicated to show the direction of liver bud migration or hepatic epithelium; a, anterior; p, posterior; d, dorsal; v, ventral. (G-L) NRTN acts as a chemoattractant for the liver bud in vitro . Isolated liver buds (lb) from HH16 chick embryos were cultured for 24 h in a collagen gel with beads soaked in BSA as a control (G, J), in GDNF (H, K), or in NRTN (I, L). The red arrow in (L) shows the liver bud migrating toward the NRTN-soaked bead. The blue arrows in (J) and (K ) show the gaps between the liver buds. Scale bars are 100μm.