title: Zeb1 controls neuron differentiation and germinal zone exit by a mesenchymal-epithelial-like transition.
abstract: In the developing mammalian brain, differentiating neurons mature morphologically via neuronal polarity programs. Despite discovery of polarity pathways acting concurrently with differentiation, it's unclear how neurons traverse complex polarity transitions or how neuronal progenitors delay polarization during development. We report that zinc finger and homeobox transcription factor-1 (Zeb1), a master regulator of epithelial polarity, controls neuronal differentiation by transcriptionally repressing polarity genes in neuronal progenitors. Necessity-sufficiency testing and functional target screening in cerebellar granule neuron progenitors (GNPs) reveal that Zeb1 inhibits polarization and retains progenitors in their germinal zone (GZ). Zeb1 expression is elevated in the Sonic Hedgehog (SHH) medulloblastoma subgroup originating from GNPs with persistent SHH activation. Restored polarity signaling promotes differentiation and rescues GZ exit, suggesting a model for future differentiative therapies. These results reveal unexpected parallels between neuronal differentiation and mesenchymal-to-epithelial transition and suggest that active polarity inhibition contributes to altered GZ exit in pediatric brain cancers.
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, United States.
authors.forename: Shalini
authors.initials: S
authors.lastname: Singh
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, United States.
authors.forename: Danielle
authors.initials: D
authors.lastname: Howell
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, United States.
authors.forename: Niraj
authors.initials: N
authors.lastname: Trivedi
authors.affiliation: Universite Denis Diderot (Paris 7), Paris, France.
authors.forename: Ketty
authors.initials: K
authors.lastname: Kessler
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, United States.
authors.forename: Taren
authors.initials: T
authors.lastname: Ong
authors.affiliation: Department of Molecular Neurobiology, Instituto Gulbenkian de Ciência Oeiras, Oeiras, Portugal.
authors.forename: Pedro
authors.initials: P
authors.lastname: Rosmaninho
authors.affiliation: Department of Molecular Neurobiology, Instituto Gulbenkian de Ciência Oeiras, Oeiras, Portugal.
authors.forename: Alexandre Asf
authors.identifier: 0000-0002-2794-0508
authors.initials: AA
authors.lastname: Raposo
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, United States.
authors.forename: Giles
authors.initials: G
authors.lastname: Robinson
authors.affiliation: Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, United States.
authors.forename: Martine F
authors.initials: MF
authors.lastname: Roussel
authors.affiliation: Department of Molecular Neurobiology, Instituto Gulbenkian de Ciência Oeiras, Oeiras, Portugal.
authors.forename: Diogo S
authors.initials: DS
authors.lastname: Castro
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, United States.
authors.forename: David J
authors.identifier: 0000-0001-8481-0403
authors.initials: DJ
authors.lastname: Solecki
mesh_terms: D000818:Animals; D001921:Brain / Q000196:embryology; D002454:Cell Differentiation; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D009474:Neurons / Q000502:physiology*; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C519422:ZEB1 protein, mouse; D000071799:Zinc Finger E-box-Binding Homeobox 1
keywords: PAR polarity complex; cell adhesion; developmental biology; mesenchymal-epithelial transition; mouse; neuronal differentition; neuronal migration; neuronal polarity; neuroscience; stem cells