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Katherine C. Gates, Jeremy D. Cantlon, Lindsey N. Goetzmann, Russell V. Anthony, Proline Rich 15 Regulates Trophoblast Proliferation and Differentiation., Biology of Reproduction, Volume 87, Issue Suppl_1, 1 August 2012, Page 378, https://doi.org/10.1093/biolreprod/87.s1.378
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Proline rich 15 (PRR15) is a small nuclear protein expressed by the trophoblast during early gestation in several mammalian species, including humans, mice, cattle, and horses. The expression profile in the sheep conceptus reveals a peak in expression at day 16 of gestation. This coincides with a halt in elongation of the conceptus, and the initial apposition to the endometrium. Additional research demonstrated increased PRR15 in non-proliferating cell populations, indicating it may be involved in terminal differentiation. Lentiviral-mediated knockdown of PRR15 in ovine trophectoderm led to demise of the embryo by gestational day 15. This provides compelling evidence that PRR15 is a critical factor during this window of development where proliferation gives way to differentiation of the trophoblast cells. The aims of these experiments were to determine the effect of PRR15 knockdown on trophoblast gene expression, as well as trophoblast proliferation and survival. The human first trimester trophoblast cell line, ACH-3P, was infected with control lentivirus (LL3.7) and lentivirus expressing a short hairpin (sh)RNA to target PRR15 mRNA for degradation, resulting in a 68% decrease in PRR15 mRNA (p<0.001). Microarray analysis of these cell lines (n=3 per group) revealed changes in gene expression pathways related to cancer, focal adhesion, and p53 signaling. We selected 20 genes for validation of mRNA levels by quantitative real-time RT-PCR, 18 (90%) of which gave results consistent with the microarray analysis. These changes included significant up-regulation of GDF15, a cytokine increased in pregnancies with preeclampsia. We evaluated GDF15 mRNA concentrations during early ovine gestation and found that GDF15 was low during peak PRR15 expression, then increased significantly at day 30 when PRR15 was nearly undetectable. Proliferation decreased in the absence of PRR15, suggesting that PRR15 may be required for driving trophoblast proliferation and survival during early development of the placenta. This project was supported by Agriculture and Food Research Initiative Competitive Grant no. 2009-65203-05670 from the USDA National Institute of Food and Agriculture.
