title: Four and a Half LIM Domains 1b (Fhl1b) Is Essential for Regulating the Liver versus Pancreas Fate Decision and for β-Cell Regeneration.
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. We have identified four and a half LIM domains 1b (fhl1b), which is primarily expressed in the prospective liver anlage, as a novel target of Bmp2b signaling. fhl1b depletion compromised liver specification and enhanced induction of pancreatic cells from endodermal progenitors. Conversely, overexpression of fhl1b favored liver specification and inhibited induction of pancreatic cells. By single-cell lineage tracing, we showed that fhl1b depletion led lateral endodermal cells, destined to become liver cells, to become pancreatic cells. Reversely, when fhl1b was overexpressed, medially located endodermal cells, fated to differentiate into pancreatic and intestinal cells, contributed to the liver by directly or indirectly modulating the discrete levels of pdx1 expression in endodermal progenitors. Moreover, loss of fhl1b increased the regenerative capacity of β-cells by increasing pdx1 and neurod expression in the hepatopancreatic ductal system. Altogether, these data reveal novel and critical functions of Fhl1b in the hepatic versus pancreatic fate decision and in β-cell regeneration.
authors: School of Biology and the Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, United States of America.
authors: Jin
authors: J
authors: Xu
authors: Max Planck Institute for Polymer Research, Mainz, Germany.
authors: Jiaxi
authors: J
authors: Cui
authors: Max Planck Institute for Polymer Research, Mainz, Germany.
authors: Aranzazu
authors: A
authors: Del Campo
authors: School of Biology and the Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, United States of America.
authors: Chong Hyun
authors: CH
authors: Shin
mesh_terms: D000818:Animals; D019521:Body Patterning; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D019070:Cell Lineage; D004707:Endoderm / Q000166:cytology; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D060588:LIM Domain Proteins / Q000378:metabolism*; D008099:Liver / Q000196:embryology* / Q000378:metabolism; D008954:Models, Biological; D012038:Regeneration; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000378:metabolism*
chemical_list: D055415:Bone Morphogenetic Protein 4; C000609100:Fhl1b protein, zebrafish; D060588:LIM Domain Proteins; D029961:Zebrafish Proteins