OR53-4 Deficiency of the placenta-specific tristetraprolin family member ZFP36L3 in the mouse identifies possible mRNA targets and an unexpected link to placental iron metabolism

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR53-Transcriptional Regulators & Epigenetic Control
Basic/Translational
Tuesday, June 18, 2013: 9:15 AM-10:45 AM
Presentation Start Time: 10:00 AM
Room 133 (Moscone Center)
Deborah Stumpo*1 and Perry Justin Blackshear2
1NIEHS, Research Triangle Park, NC, 2NIEHS, Research Triangle Pk, NC
Deficiency of the placenta-specific tristetraprolin family member ZFP36L3 in the mouse identifies possible mRNA targets and an unexpected link to placental iron metabolism

Deborah J. Stumpo and Perry J. Blackshear

From the Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709

The ZFP36L3 protein is a member of the tristetraprolin (TTP) family of CCCH tandem zinc finger proteins.  These RNA binding proteins are known to promote mRNA deadenylation and decay after binding to AU-rich elements in target mRNAs.  ZFP36L3 is the fourth and final member of the family to be discovered in mice; it is expressed only in rodents, and only in extra-embryonic fetal tissues such as the placenta and yolk sac (1,2).  In the rodent placenta, expression is largely limited to the syncytiotrophoblast region and the trophoblast giant cells.  Knockout (KO) of this gene in mice results in significantly decreased neonatal survival rates, but no apparent morphological changes in the placenta or surviving offspring.  The gene appears to be paternally imprinted, with profound parent of origin effects on gene expression.  Gene expression analysis of KO placentas using deep sequencing and digital barcoding revealed a large number of significantly affected transcripts, with many of the upregulated mRNAs encoding transporters and other proteins important for materno-fetal nutrient uptake.  Many of these contained signature binding sequences for TTP family RNA binding proteins. There was an unexpected, profound decrease in expression of the Tfrc transcript; this encodes the type 1 transferrin receptor, which is thought to be the sole mediator of placental iron uptake from the maternal circulation.  The decrease in Tfrc mRNA levels was accompanied by decreased iron stores in the KO fetus, raising the possibility that this intrauterine deficiency might have deleterious consequences in later life.  Stability of the potential ZFP36L3-affected transcripts was tested in differentiated trophoblast stem cells from wild-type and KO mice.  Many of the transcripts stabilized under conditions of ZFP36L3 deficiency were the same as those that accumulated abnormally in the intact KO placenta.  These target transcripts including mRNAs encoding growth factors, transcription factors, metabolic enzymes and nutrient transporters.  These findings indicate that ZFP36L3 is an important regulator of post-transcriptional gene expression in the placenta, and identify many apparent direct mRNA targets of this protein.  An important topic for future work is to determine whether one or more of the three TTP family members expressed in human placenta plays the same role in regulating placental mRNA stability and ultimate expression.

1.  Blackshear, P.J., et al., Zfp36l3, a rodent X chromosome gene encoding a placenta-specific member of the Tristetraprolin family of CCCH tandem zinc finger proteins. Biol Reprod, 2005. 73(2): p. 297-307. 2.  Frederick, E.D., S.B. Ramos, and P.J. Blackshear, A unique C-terminal repeat domain maintains the cytosolic localization of the placenta-specific tristetraprolin family member ZFP36L3. J Biol Chem, 2008. 283(21): p. 14792-800.

Nothing to Disclose: DS, PJB

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Supported by the Intramural Research Program of the NIH, NIEHS.