Four and a Half LIM Domains 1b (Fhl1b) Is Essential for Regulating the Liver versus Pancreas Fate Decision and for beta-Cell Regeneration.

Authors:
C. Shin 1 ; J. Xu 1 ; J. Cui 2 ; A. Del Campo 2


Institutes
1) School of Biology and the Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, United States of America; 2) Max Planck Institute for Polymer Research, Mainz, Germany.


Abstract:

The liver and pancreas originate from overlapping embryonic regions, and single-cell lineage tracing in zebrafish has shown that Bone morphogenetic protein 2b (Bmp2b) signaling is essential for determining the fate of bipotential hepatopancreatic progenitors towards the liver or pancreas. Despite its pivotal role, the gene regulatory networks functioning downstream of Bmp2b signaling in this process are poorly understood. Through transcriptome profiling of endodermal tissues exposed to increased or decreased Bmp2b signaling, we have discovered the zebrafish gene four and a half LIM domains 1b (fhl1b) as a novel target of Bmp2b signaling. fhl1b is primarily expressed in the prospective liver anlage. Loss- and gain-of-function analyses indicate that Fhl1b suppresses specification of the pancreas and induces the liver. By single-cell lineage tracing, we showed that depletion of fhl1b caused a liver-to-pancreas fate switch, while fhl1b overexpression redirected pancreatic progenitors to become liver cells. At later stages, Fhl1b regulates regeneration of insulin-secreting beta-cells by directly or indirectly modulating pdx1 and neurod expression in the hepatopancreatic ductal system. Therefore, our work provides a novel paradigm of how Bmp signaling regulates the hepatic versus pancreatic fate decision and beta-cell regeneration through its novel target Fhl1b.