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Molecular and Cellular Biology, May 2009, p. 2762-2776, Vol. 29, No. 10
0270-7306/09/$08.00+0     doi:10.1128/MCB.01393-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The RNA-Binding Protein Elavl1/HuR Is Essential for Placental Branching Morphogenesis and Embryonic Development{triangledown} ,{dagger}

Vicky Katsanou,1,{ddagger} Stavros Milatos,1,{ddagger} Anthie Yiakouvaki,1 Nikos Sgantzis,1 Anastasia Kotsoni,1 Maria Alexiou,1 Vaggelis Harokopos,1 Vassilis Aidinis,1 Myriam Hemberger,2 and Dimitris L. Kontoyiannis1*

Institute of Immunology, Biomedical Sciences Research Center Alexander Fleming, 16672 Vari, Greece,1 Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, United Kingdom2

Received 5 September 2008/ Returned for modification 20 October 2008/ Accepted 10 March 2009

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.

* Corresponding author. Mailing address: Institute of Immunology, BSRC Alexander Fleming, 34 Al. Fleming Str., 166 72 Vari, Greece. Phone: 0030-210-9654335. Fax: 0030-210-9654955. E-mail: kontoyiannis{at}fleming.gr

{triangledown} Published ahead of print on 23 March 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} These authors contributed equally.

Molecular and Cellular Biology, May 2009, p. 2762-2776, Vol. 29, No. 10
0270-7306/09/$08.00+0     doi:10.1128/MCB.01393-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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