title: Primary Cilium-Autophagy-Nrf2 (PAN) Axis Activation Commits Human Embryonic Stem Cells to a Neuroectoderm Fate.
abstract: Under defined differentiation conditions, human embryonic stem cells (hESCs) can be directed toward a mesendoderm (ME) or neuroectoderm (NE) fate, the first decision during hESC differentiation. Coupled with lineage-specific G1 lengthening, a divergent ciliation pattern emerged within the first 24 hr of induced lineage specification, and these changes heralded a neuroectoderm decision before any neural precursor markers were expressed. By day 2, increased ciliation in NE precursors induced autophagy that resulted in the inactivation of Nrf2 and thereby relieved transcriptional activation of OCT4 and NANOG. Nrf2 binds directly to upstream regions of these pluripotency genes to promote their expression and repress NE derivation. Nrf2 suppression was sufficient to rescue poorly neurogenic iPSC lines. Only after these events had been initiated did neural precursor markers get expressed at day 4. Thus, we have identified a primary cilium-autophagy-Nrf2 (PAN) control axis coupled to cell-cycle progression that directs hESCs toward NE.
authors.affiliation: Department of Molecular Cellular Developmental Biology, Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.
authors.forename: Jiwon
authors.initials: J
authors.lastname: Jang
authors.affiliation: Department of Molecular Cellular Developmental Biology, Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.
authors.forename: Yidi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Molecular Cellular Developmental Biology, Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Lalli
authors.affiliation: Department of Molecular Cellular Developmental Biology, Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.
authors.forename: Elmer
authors.initials: E
authors.lastname: Guzman
authors.affiliation: Department of Molecular Cellular Developmental Biology, Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.
authors.forename: Sirie E
authors.initials: SE
authors.lastname: Godshalk
authors.affiliation: Department of Molecular Cellular Developmental Biology, Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Molecular Cellular Developmental Biology, Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA. Electronic address: kosik@lifesci.ucsb.edu.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Kosik
mesh_terms: D001343:Autophagy; D002453:Cell Cycle; D002923:Cilia / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000166:cytology*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D000071317:Nanog Homeobox Protein; D054258:Neural Plate / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000235:genetics; D039904:Pluripotent Stem Cells / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C486780:NANOG protein, human; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human