Zeb1 controls neuron differentiation and germinal zone exit by a mesenchymal-epithelial-like transition

Detalhes bibliográficos
Autor(a) principal: Singh, Shalini
Data de Publicação: 2016
Outros Autores: Howell, Danielle, Trivedi, Niraj, Kessler, Ketty, Ong, Taren, Rosmaninho, Pedro, Raposo, Alexandre ASF, Robinson, Giles, Roussel, Martine F, Castro, Diogo S, Solecki, David J
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10400.7/738
Resumo: 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.
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spelling Zeb1 controls neuron differentiation and germinal zone exit by a mesenchymal-epithelial-like transitionDevelopment BiologyStem CellsNeurosciencecell adhesionmesenchymal-epithelial transitionMouseneuronal differentitionneuronal migrationneuronal polarityPAR polarity complexIn 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.National Institute of Neurological Disorders and Stroke grant: (1R01NS066936); March of Dimes Foundation grant: (#1-FY12-455).eLife Sciences PublicationsARCASingh, ShaliniHowell, DanielleTrivedi, NirajKessler, KettyOng, TarenRosmaninho, PedroRaposo, Alexandre ASFRobinson, GilesRoussel, Martine FCastro, Diogo SSolecki, David J2017-03-06T16:20:11Z2016-05-142016-05-14T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfimage/jpegimage/jpegimage/jpegimage/jpegimage/jpegimage/jpegimage/jpegimage/jpegimage/jpegimage/jpegimage/jpegimage/jpegimage/jpegimage/jpegapplication/vnd.ms-excelapplication/vnd.openxmlformats-officedocument.spreadsheetml.sheetapplication/vnd.ms-excelhttp://hdl.handle.net/10400.7/738engeLife 2016;5:e1271710.7554/eLife.12717info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2022-11-29T14:35:08Zoai:arca.igc.gulbenkian.pt:10400.7/738Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T16:11:57.998433Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Zeb1 controls neuron differentiation and germinal zone exit by a mesenchymal-epithelial-like transition
title Zeb1 controls neuron differentiation and germinal zone exit by a mesenchymal-epithelial-like transition
spellingShingle Zeb1 controls neuron differentiation and germinal zone exit by a mesenchymal-epithelial-like transition
Singh, Shalini
Development Biology
Stem Cells
Neuroscience
cell adhesion
mesenchymal-epithelial transition
Mouse
neuronal differentition
neuronal migration
neuronal polarity
PAR polarity complex
title_short Zeb1 controls neuron differentiation and germinal zone exit by a mesenchymal-epithelial-like transition
title_full Zeb1 controls neuron differentiation and germinal zone exit by a mesenchymal-epithelial-like transition
title_fullStr Zeb1 controls neuron differentiation and germinal zone exit by a mesenchymal-epithelial-like transition
title_full_unstemmed Zeb1 controls neuron differentiation and germinal zone exit by a mesenchymal-epithelial-like transition
title_sort Zeb1 controls neuron differentiation and germinal zone exit by a mesenchymal-epithelial-like transition
author Singh, Shalini
author_facet Singh, Shalini
Howell, Danielle
Trivedi, Niraj
Kessler, Ketty
Ong, Taren
Rosmaninho, Pedro
Raposo, Alexandre ASF
Robinson, Giles
Roussel, Martine F
Castro, Diogo S
Solecki, David J
author_role author
author2 Howell, Danielle
Trivedi, Niraj
Kessler, Ketty
Ong, Taren
Rosmaninho, Pedro
Raposo, Alexandre ASF
Robinson, Giles
Roussel, Martine F
Castro, Diogo S
Solecki, David J
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv ARCA
dc.contributor.author.fl_str_mv Singh, Shalini
Howell, Danielle
Trivedi, Niraj
Kessler, Ketty
Ong, Taren
Rosmaninho, Pedro
Raposo, Alexandre ASF
Robinson, Giles
Roussel, Martine F
Castro, Diogo S
Solecki, David J
dc.subject.por.fl_str_mv Development Biology
Stem Cells
Neuroscience
cell adhesion
mesenchymal-epithelial transition
Mouse
neuronal differentition
neuronal migration
neuronal polarity
PAR polarity complex
topic Development Biology
Stem Cells
Neuroscience
cell adhesion
mesenchymal-epithelial transition
Mouse
neuronal differentition
neuronal migration
neuronal polarity
PAR polarity complex
description 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.
publishDate 2016
dc.date.none.fl_str_mv 2016-05-14
2016-05-14T00:00:00Z
2017-03-06T16:20:11Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10400.7/738
url http://hdl.handle.net/10400.7/738
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv eLife 2016;5:e12717
10.7554/eLife.12717
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
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image/jpeg
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dc.publisher.none.fl_str_mv eLife Sciences Publications
publisher.none.fl_str_mv eLife Sciences Publications
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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