title: The RNA-binding protein Elavl1/HuR is essential for placental branching morphogenesis and embryonic development.
abstract: HuR is an RNA-binding protein implicated in a diverse array of pathophysiological processes due to its effects on the posttranscriptional regulation of AU- and U-rich mRNAs. Here we reveal HuR's requirement in embryonic development through its genetic ablation. Obligatory HuR-null embryos exhibited a stage retardation phenotype and failed to survive beyond midgestation. By means of conditional transgenesis, we restricted HuR's mutation in either embryonic or endothelial compartments to demonstrate that embryonic lethality is consequent to defects in extraembryonic placenta. HuR's absence impaired the invagination of allantoic capillaries into the chorionic trophoblast layer and the differentiation of syncytiotrophoblast cells that control the morphogenesis and vascularization of the placental labyrinth and fetal support. HuR-null embryos rescued from these placental defects proceeded to subsequent developmental stages but displayed defects in skeletal ossification, fusions in limb elements, and asplenia. By coupling gene expression measurements, data meta-analysis, and HuR-RNA association assays, we identified transcription and growth factor mRNAs controlled by HuR, primarily at the posttranscriptional level, to guide morphogenesis, specification, and patterning. Collectively, our data demonstrate the dominant role of HuR in organizing gene expression programs guiding placental labyrinth morphogenesis, skeletal specification patterns, and splenic ontogeny.
authors.affiliation: Institute of Immunology, Biomedical Sciences Research Center Alexander Fleming, 16672 Vari, Greece.
authors.forename: Vicky
authors.initials: V
authors.lastname: Katsanou
authors.forename: Stavros
authors.initials: S
authors.lastname: Milatos
authors.forename: Anthie
authors.initials: A
authors.lastname: Yiakouvaki
authors.forename: Nikos
authors.initials: N
authors.lastname: Sgantzis
authors.forename: Anastasia
authors.initials: A
authors.lastname: Kotsoni
authors.forename: Maria
authors.initials: M
authors.lastname: Alexiou
authors.forename: Vaggelis
authors.initials: V
authors.lastname: Harokopos
authors.forename: Vassilis
authors.initials: V
authors.lastname: Aidinis
authors.forename: Myriam
authors.initials: M
authors.lastname: Hemberger
authors.forename: Dimitris L
authors.initials: DL
authors.lastname: Kontoyiannis
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D005260:Female; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009024:Morphogenesis; D009139:Musculoskeletal Abnormalities / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D010920:Placenta / Q000033:anatomy & histology / Q000196:embryology; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000002:abnormalities / Q000196:embryology
chemical_list: D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins