title: EpCAM is an endoderm-specific Wnt derepressor that licenses hepatic development.
abstract: Mechanisms underlying cell-type-specific response to morphogens or signaling molecules during embryonic development are poorly understood. To learn how response to the liver-inductive Wnt2bb signal is achieved, we identify an endoderm-enriched, single transmembrane protein, epithelial-cell-adhesion-molecule (EpCAM), as an endoderm-specific Wnt derepressor in zebrafish. hi2151/epcam mutants exhibit defective liver development similar to prt/wnt2bb mutants. EpCAM directly binds to Kremen1 and disrupts the Kremen1-Dickkopf2 (Dkk2) interaction, which prevents Kremen1-Dkk2-mediated removal of Lipoprotein-receptor-related protein 6 (Lrp6) from the cell surface. These data lead to a model in which EpCAM derepresses Lrp6 and cooperates with Wnt ligand to activate Wnt signaling through stabilizing membrane Lrp6 and allowing Lrp6 clustering into active signalosomes. Thus, EpCAM cell autonomously licenses and cooperatively activates Wnt2bb signaling in endodermal cells. Our results identify EpCAM as the key molecule and its functional mechanism to confer endodermal cells the competence to respond to the liver-inductive Wnt2bb signal.
authors.affiliation: Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Laboratory of Molecular Developmental Biology, School of Life Sciences, Southwest University, Beibei, 400715 Chongqing, China.
authors.forename: Huiqiang
authors.initials: H
authors.lastname: Lu
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.forename: Yun
authors.initials: Y
authors.lastname: Yang
authors.forename: Wenchao
authors.initials: W
authors.lastname: Shi
authors.forename: Lingfei
authors.initials: L
authors.lastname: Luo
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002462:Cell Membrane / Q000378:metabolism; D004707:Endoderm / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D008099:Liver / Q000166:cytology* / Q000378:metabolism; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C524037:EpCAM protein, zebrafish; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D051153:Wnt Proteins; D029961:Zebrafish Proteins; C492033:wnt2ba protein, zebrafish