title: FOSL1 is integral to establishing the maternal-fetal interface.
abstract: Remodeling of uterine spiral arteries by trophoblast cells is a requisite process for hemochorial placentation and successful pregnancy. The rat exhibits deep intrauterine trophoblast invasion and accompanying trophoblast-directed vascular modification. The involvement of phosphatidylinositol 3 kinase (PI3K), AKT, and Fos-like antigen 1 (FOSL1) in regulating invasive trophoblast and hemochorial placentation was investigated using Rcho-1 trophoblast stem cells and rat models. Disruption of PI3K/AKT with small-molecule inhibitors interfered with the differentiation-dependent elaboration of a signature invasive-vascular remodeling trophoblast gene expression profile and trophoblast invasion. AKT isoform-specific knockdown also affected the signature invasive-vascular remodeling trophoblast gene expression profile. Nuclear FOSL1 increased during trophoblast cell differentiation in a PI3K/AKT-dependent manner. Knockdown of FOSL1 disrupted the expression of a subset of genes associated with the invasive-vascular remodeling trophoblast phenotype, including the matrix metallopeptidase 9 gene (Mmp9). FOSL1 was shown to occupy regions of the Mmp9 promoter in trophoblast cells critical for the regulation of Mmp9 gene expression. Inhibition of FOSL1 expression also abrogated trophoblast invasion, as assessed in vitro and following in vivo trophoblast-specific lentivirally delivered FOSL1 short hairpin RNA (shRNA). In summary, FOSL1 is a key downstream effector of the PI3K/AKT signaling pathway responsible for development of trophoblast lineages integral to establishing the maternal-fetal interface.
authors.affiliation: Institute for Reproductive Health and Regenerative Medicine, Department of Pathology & Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
authors.forename: Lindsey N
authors.initials: LN
authors.lastname: Kent
authors.forename: M A Karim
authors.initials: MA
authors.lastname: Rumi
authors.forename: Kaiyu
authors.initials: K
authors.lastname: Kubota
authors.forename: Dong-Soo
authors.initials: DS
authors.lastname: Lee
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Soares
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002465:Cell Movement; D006224:Cricetinae; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D008431:Maternal-Fetal Exchange; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010920:Placenta / Q000166:cytology / Q000502:physiology*; D010929:Placentation; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism / Q000502:physiology; D014327:Trophoblasts / Q000378:metabolism / Q000502:physiology; D000099169:Fos-Related Antigen 1
chemical_list: D007527:Isoenzymes; D020780:Matrix Metalloproteinase 9; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D016760:Proto-Oncogene Proteins c-fos; D000099169:Fos-Related Antigen 1