title: Geminin promotes an epithelial-to-mesenchymal transition in an embryonic stem cell model of gastrulation.
abstract: Geminin is a nuclear protein that performs the related functions of modulating cell cycle progression by binding Cdt1, and controlling differentiation by binding transcription factors. Since embryonic stem cells (ESC) and the epiblast share a similar gene expression profile and an attenuated cell cycle, ESC form an accessible and tractable model system to study lineage choice at gastrulation. We derived several ESC lines in which Geminin can be inducibly expressed, and employed short hairpin RNAs targeting Geminin. As in the embryo, a lack of Geminin protein resulted in DNA damage and cell death. In monolayer culture, in defined medium, Geminin supported neural differentiation; however, in three-dimensional culture, overexpression of Geminin promoted mesendodermal differentiation and epithelial-to-mesenchymal transition. In vitro, ESC overexpressing Geminin rapidly recolonized a wound, downregulated E-cadherin expression, and activated Wnt signaling. We suggest that Geminin may promote differentiation via binding Groucho/TLE proteins and upregulating canonical Wnt signaling.
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109-2200, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Slawny
authors.forename: K Sue
authors.initials: KS
authors.lastname: O'Shea
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D004318:Doxycycline / Q000494:pharmacology; D058732:Embryoid Bodies / Q000166:cytology / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D054262:Gastrulation / Q000235:genetics*; D064248:Geminin; D015870:Gene Expression / Q000187:drug effects; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D022661:RNA, Untranslated; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013724:Teratoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D015820:Cadherins; D018797:Cell Cycle Proteins; D064248:Geminin; C577997:Gmnn protein, mouse; C110853:Gt(ROSA)26Sor non-coding RNA, mouse; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D009687:Nuclear Proteins; D011506:Proteins; D022661:RNA, Untranslated; D004318:Doxycycline