The RNA-binding protein Elavl1/HuR is essential for placental branching morphogenesis and embryonic development.
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.
Katsanou
Vicky
V
Institute of Immunology, Biomedical Sciences Research Center Alexander Fleming, 16672 Vari, Greece.
Milatos
Stavros
S
Yiakouvaki
Anthie
A
Sgantzis
Nikos
N
Kotsoni
Anastasia
A
Alexiou
Maria
M
Harokopos
Vaggelis
V
Aidinis
Vassilis
V
Hemberger
Myriam
M
Kontoyiannis
Dimitris L
DL
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
D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins