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Proc Natl Acad Sci U S A. 2014 Sep 23;111(38):13882-7. doi: 10.1073/pnas.1411674111. Epub 2014 Sep 9.

PreImplantation factor promotes neuroprotection by targeting microRNA let-7.

Author information

1
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510; Department of Obstetrics and Gynecology, University Hospital, 3010 Bern, Switzerland;
2
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510; Department of Surgical Oncology, Affiliated Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, People's Republic of China;
3
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510; Department of Obstetrics and Gynecology, Tangshan Gongren Hospital, Tangshan, Hebei 063000, People's Republic of China;
4
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510; Department of Gynecology and Obstetrics, Chinese PLA General Hospital, Beijing 100853, People's Republic of China;
5
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510; Department of Obstetrics and Gynecology, Jilin University, Changchun, Jilin 130021, People's Republic of China;
6
Department of Clinical Research, University of Bern, 3012 Bern, Switzerland;
7
Department of Obstetrics and Gynecology, University Hospital, 3010 Bern, Switzerland; Department of Clinical Research, University of Bern, 3012 Bern, Switzerland;
8
Society for the Investigation of Early Pregnancy, Cherry Hill, NJ 08003; BioIncept, LLC, Cherry Hill, NJ 08003; and.
9
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510; Women and Children's Center for Blood Disorders, Yale University School of Medicine, New Haven, CT 06510 michael.paidas@yale.edu yingqun.huang@yale.edu.
10
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510; michael.paidas@yale.edu yingqun.huang@yale.edu.

Abstract

Dysfunction and loss of neurons are the major characteristics of CNS disorders that include stroke, multiple sclerosis, and Alzheimer's disease. Activation of the Toll-like receptor 7 by extracellular microRNA let-7, a highly expressed microRNA in the CNS, induces neuronal cell death. Let-7 released from injured neurons and immune cells acts on neighboring cells, exacerbating CNS damage. Here we show that a synthetic peptide analogous to the mammalian PreImplantation factor (PIF) secreted by developing embryos and which is present in the maternal circulation during pregnancy inhibits the biogenesis of let-7 in both neuronal and immune cells of the mouse. The synthetic peptide, sPIF, destabilizes KH-type splicing regulatory protein (KSRP), a key microRNA-processing protein, in a Toll-like receptor 4 (TLR4)-dependent manner, leading to decreased production of let-7. Furthermore, s.c. administration of sPIF into neonatal rats following hypoxic-ischemic brain injury robustly rescued cortical volume and number of neurons and decreased the detrimental glial response, as is consistent with diminished levels of KSRP and let-7 in sPIF-treated brains. Our results reveal a previously unexpected mechanism of action of PIF and underscore the potential clinical utility of sPIF in treating hypoxic-ischemic brain damage. The newly identified PIF/TLR4/KSRP/let-7 regulatory axis also may operate during embryo implantation and development.

PMID:
25205808
PMCID:
PMC4183321
DOI:
10.1073/pnas.1411674111
[Indexed for MEDLINE]
Free PMC Article

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