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Molecular and Cellular Biology, July 2004, p. 6445-6455, Vol. 24, No. 14
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.14.6445-6455.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Chorioallantoic Fusion Defects and Embryonic Lethality Resulting from Disruption of Zfp36L1, a Gene Encoding a CCCH Tandem Zinc Finger Protein of the Tristetraprolin Family

Deborah J. Stumpo,1 Noah A. Byrd,2 Ruth S. Phillips,1 Sanjukta Ghosh,1 Robert R. Maronpot,3 Trisha Castranio,4 Erik N. Meyers,2 Yuji Mishina,4 and Perry J. Blackshear1,5,6*

Laboratory of Signal Transduction,1 Laboratory of Experimental Pathology,3 Laboratory of Reproductive and Developmental Toxicology,4 Office of Clinical Research, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709,5 Departments of Medicine and Biochemistryof,6 Pediatrics and Cell Biology, Duke University Medical Center, Durham, North Carolina 277102

Received 2 September 2003/ Returned for modification 14 October 2003/ Accepted 1 March 2004

The mouse gene Zfp36L1 encodes zinc finger protein 36-like 1 (Zfp36L1), a member of the tristetraprolin (TTP) family of tandem CCCH finger proteins. TTP can bind to AU-rich elements within the 3'-untranslated regions of the mRNAs encoding tumor necrosis factor (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), leading to accelerated mRNA degradation. TTP knockout mice exhibit an inflammatory phenotype that is largely due to increased TNF secretion. Zfp36L1 has activities similar to those of TTP in cellular RNA destabilization assays and in cell-free RNA binding and deadenylation assays, suggesting that it may play roles similar to those of TTP in mammalian physiology. To address this question we disrupted Zfp36L1 in mice. All knockout embryos died in utero, most by approximately embryonic day 11 (E11). Failure of chorioallantoic fusion occurred in about two-thirds of cases. Even when fusion occurred, by E10.5 the affected placentas exhibited decreased cell division and relative atrophy of the trophoblast layers. Although knockout embryos exhibited neural tube abnormalities and increased apoptosis within the neural tube and also generalized runting, these and other findings may have been due to deficient placental function. Embryonic expression of Zfp36L1 at E8.0 was greatest in the allantois, consistent with a potential role in chorioallantoic fusion. Fibroblasts derived from knockout embryos had apparently normal levels of fully polyadenylated compared to deadenylated GM-CSF mRNA and normal rates of turnover of this mRNA species, both sensitive markers of TTP deficiency in cells. We postulate that lack of Zfp36L1 expression during mid-gestation results in the abnormal stabilization of one or more mRNAs whose encoded proteins lead directly or indirectly to abnormal placentation and fetal death.

* Corresponding author. Mailing address: A2-05 NIEHS, 111 Alexander Dr., Research Triangle Park, NC 27709. Phone: (919) 541-4899. Fax: (919) 541-4571. E-mail: Black009{at}niehs.nih.gov.

Molecular and Cellular Biology, July 2004, p. 6445-6455, Vol. 24, No. 14
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.14.6445-6455.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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