title: PreImplantation factor promotes neuroprotection by targeting microRNA let-7.
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.
authors.affiliation: 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;
authors.forename: Martin
authors.initials: M
authors.lastname: Mueller
authors.affiliation: 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;
authors.forename: Jichun
authors.initials: J
authors.lastname: Zhou
authors.affiliation: 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;
authors.forename: Lihua
authors.initials: L
authors.lastname: Yang
authors.affiliation: 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;
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: 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;
authors.forename: Fuju
authors.initials: F
authors.lastname: Wu
authors.affiliation: Department of Clinical Research, University of Bern, 3012 Bern, Switzerland;
authors.forename: Andreina
authors.initials: A
authors.lastname: Schoeberlein
authors.affiliation: Department of Obstetrics and Gynecology, University Hospital, 3010 Bern, Switzerland; Department of Clinical Research, University of Bern, 3012 Bern, Switzerland;
authors.forename: Daniel
authors.initials: D
authors.lastname: Surbek
authors.affiliation: Society for the Investigation of Early Pregnancy, Cherry Hill, NJ 08003; BioIncept, LLC, Cherry Hill, NJ 08003; and.
authors.forename: Eytan R
authors.initials: ER
authors.lastname: Barnea
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Paidas
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510; michael.paidas@yale.edu yingqun.huang@yale.edu.
authors.forename: Yingqun
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000166:cytology / Q000378:metabolism*; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism; D010064:Embryo Implantation / Q000502:physiology*; D005260:Female; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
chemical_list: C507913:Khsrp protein, mouse; C548145:MIRNLET7 microRNA, rat; D035683:MicroRNAs; D010455:Peptides; D016601:RNA-Binding Proteins; C493487:Tlr4 protein, mouse; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D015534:Trans-Activators; C542687:mirnlet7 microRNA, mouse; C561617:preimplantation factor, mouse