title: Liver-Enriched Gene 1, a Glycosylated Secretory Protein, Binds to FGFR and Mediates an Anti-stress Pathway to Protect Liver Development in Zebrafish.
abstract: Unlike mammals and birds, teleost fish undergo external embryogenesis, and therefore their embryos are constantly challenged by stresses from their living environment. These stresses, when becoming too harsh, will cause arrest of cell proliferation, abnormal cell death or senescence. Such organisms have to evolve a sophisticated anti-stress mechanism to protect the process of embryogenesis/organogenesis. However, very few signaling molecule(s) mediating such activity have been identified. liver-enriched gene 1 (leg1) is an uncharacterized gene that encodes a novel secretory protein containing a single domain DUF781 (domain of unknown function 781) that is well conserved in vertebrates. In the zebrafish genome, there are two copies of leg1, namely leg1a and leg1b. leg1a and leg1b are closely linked on chromosome 20 and share high homology, but are differentially expressed. In this report, we generated two leg1a mutant alleles using the TALEN technique, then characterized liver development in the mutants. We show that a leg1a mutant exhibits a stress-dependent small liver phenotype that can be prevented by chemicals blocking the production of reactive oxygen species. Further studies reveal that Leg1a binds to FGFR3 and mediates a novel anti-stress pathway to protect liver development through enhancing Erk activity. More importantly, we show that the binding of Leg1a to FGFR relies on the glycosylation at the 70th asparagine (Asn(70) or N(70)), and mutating the Asn(70) to Ala(70) compromised Leg1's function in liver development. Therefore, Leg1 plays a unique role in protecting liver development under different stress conditions by serving as a secreted signaling molecule/modulator.
authors.affiliation: MOE Key Laboratory for Molecular Animal Nutrition, College of Animal Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Minjie
authors.initials: M
authors.lastname: Hu
authors.affiliation: MOE Key Laboratory for Molecular Animal Nutrition, College of Animal Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Chunxia
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.affiliation: Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Zongbin
authors.initials: Z
authors.lastname: Cui
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: MOE Key Laboratory for Molecular Animal Nutrition, College of Animal Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Jinrong
authors.initials: J
authors.lastname: Peng
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D006031:Glycosylation; D008099:Liver / Q000196:embryology* / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D010766:Phosphorylation; D011485:Protein Binding; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000378:metabolism*; D013312:Stress, Physiological; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000737:chemistry / Q000378:metabolism*; D015053:Zygote / Q000378:metabolism
chemical_list: D029961:Zebrafish Proteins; C569822:leg1.1 protein, zebrafish; C569823:leg1.2 protein, zebrafish; D051498:Receptor, Fibroblast Growth Factor, Type 3; C496367:fgfr3 protein, zebrafish