title: LIMK1 regulates human trophoblast invasion/differentiation and is down-regulated in preeclampsia.
abstract: Successful human pregnancy requires extensive invasion of maternal uterine tissues by the placenta. Invasive extravillous trophoblasts derived from cytotrophoblast progenitors remodel maternal arterioles to promote blood flow to the placenta. In the pregnancy complication preeclampsia, extravillous trophoblasts invasion and vessel remodeling are frequently impaired, likely contributing to fetal underperfusion and maternal hypertension. We recently demonstrated in mouse trophoblast stem cells that hypoxia-inducible factor-2 (HIF-2)-dependent Lim domain kinase 1 (LIMK1) expression regulates invasive trophoblast differentiation by modulating the trophoblast cytoskeleton. Interestingly, in humans, LIMK1 activity promotes tumor cell invasion by modulating actin and microtubule integrity, as well as by modulating matrix metalloprotease processing. Here, we tested whether HIF-2α and LIMK1 expression patterns suggested similar roles in the human placenta. We found that LIMK1 immunoreactivity mirrored HIF-2α in the human placenta in utero and that LIMK1 activity regulated human cytotrophoblast cytoskeletal integrity, matrix metallopeptidase-9 secretion, invasion, and differentiation in vitro. Importantly, we also found that LIMK1 levels are frequently diminished in the preeclampsia setting in vivo. Our results therefore validate the use of mouse trophoblast stem cells as a discovery platform for human placentation disorders and suggest that LIMK1 activity helps promote human placental development in utero.
authors.affiliation: Department of Obstetrics and Gynecology, University of California, San Francisco, San Francisco, California.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Obstetrics and Gynecology, University of California, San Francisco, San Francisco, California.
authors.forename: Akitoshi
authors.initials: A
authors.lastname: Yuge
authors.affiliation: Department of Biology, San Francisco State University, San Francisco, California.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Rajah
authors.affiliation: Department of Pediatrics, University of California, San Francisco, San Francisco, California.
authors.forename: Gozde
authors.initials: G
authors.lastname: Unek
authors.affiliation: Department of Obstetrics and Gynecology, University of California, San Francisco, San Francisco, California; Department of Biomedical Sciences, University of California, San Francisco, San Francisco, California; Center for Reproductive Sciences, University of California, San Francisco, San Francisco, California.
authors.forename: Paolo F
authors.initials: PF
authors.lastname: Rinaudo
authors.affiliation: Department of Pediatrics, University of California, San Francisco, San Francisco, California; Department of Biomedical Sciences, University of California, San Francisco, San Francisco, California; Center for Reproductive Sciences, University of California, San Francisco, San Francisco, California. Electronic address: emin.maltepe@ucsf.edu.
authors.forename: Emin
authors.initials: E
authors.lastname: Maltepe
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002465:Cell Movement; D003599:Cytoskeleton / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D054461:Lim Kinases / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008856:Microscopy, Fluorescence; D010920:Placenta / Q000378:metabolism; D010929:Placentation; D011225:Pre-Eclampsia / Q000378:metabolism*; D011247:Pregnancy; D011263:Pregnancy Trimester, Third; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D014327:Trophoblasts / Q000166:cytology / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D054461:Lim Kinases; D020780:Matrix Metalloproteinase 9; D000099162:Endothelial PAS Domain-Containing Protein 1; C515892:LIMK1 protein, human; C579270:MMP9 protein, human