The level of the transcription factor Pax6 is essential for controlling the balance between neural stem cell self-renewal and neurogenesis
Neural stem cell self-renewal, neurogenesis, and cell fate determination are processes that control the generation of specific classes of neurons at the correct place and time. The transcription factor Pax6 is essential for neural stem cell proliferation, multipotency, and neurogenesis in many regio...
| Main Authors: | , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Public Library of Science
2009
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| _version_ | 1797051626570121216 |
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| author | Sansom, S Griffiths, D Faedo, A Kleinjan, D Ruan, Y Smith, J Van Heyningen, V Rubenstein, J Livesey, F |
| author_facet | Sansom, S Griffiths, D Faedo, A Kleinjan, D Ruan, Y Smith, J Van Heyningen, V Rubenstein, J Livesey, F |
| author_sort | Sansom, S |
| collection | OXFORD |
| description | Neural stem cell self-renewal, neurogenesis, and cell fate determination are processes that control the generation of specific classes of neurons at the correct place and time. The transcription factor Pax6 is essential for neural stem cell proliferation, multipotency, and neurogenesis in many regions of the central nervous system, including the cerebral cortex. We used Pax6 as an entry point to define the cellular networks controlling neural stem cell self-renewal and neurogenesis in stem cells of the developing mouse cerebral cortex. We identified the genomic binding locations of Pax6 in neocortical stem cells during normal development and ascertained the functional significance of genes that we found to be regulated by Pax6, finding that Pax6 positively and directly regulates cohorts of genes that promote neural stem cell self-renewal, basal progenitor cell genesis, and neurogenesis. Notably, we defined a core network regulating neocortical stem cell decision-making in which Pax6 interacts with three other regulators of neurogenesis, Neurog2, Ascl1, and Hes1. Analyses of the biological function of Pax6 in neural stem cells through phenotypic analyses of Pax6 gain- and loss-of-function mutant cortices demonstrated that the Pax6-regulated networks operating in neural stem cells are highly dosage sensitive. Increasing Pax6 levels drives the system towards neurogenesis and basal progenitor cell genesis by increasing expression of a cohort of basal progenitor cell determinants, including the key transcription factor Eomes/Tbr2, and thus towards neurogenesis at the expense of self-renewal. Removing Pax6 reduces cortical stem cell self-renewal by decreasing expression of key cell cycle regulators, resulting in excess early neurogenesis. We find that the relative levels of Pax6, Hes1, and Neurog2 are key determinants of a dynamic network that controls whether neural stem cells self-renew, generate cortical neurons, or generate basal progenitor cells, a mechanism that has marked parallels with the transcriptional control of embryonic stem cell self-renewal. |
| first_indexed | 2024-03-06T18:22:13Z |
| format | Journal article |
| id | oxford-uuid:06b1ab75-a08e-41b0-a660-3293ca42e838 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:22:13Z |
| publishDate | 2009 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | oxford-uuid:06b1ab75-a08e-41b0-a660-3293ca42e8382022-03-26T09:03:49ZThe level of the transcription factor Pax6 is essential for controlling the balance between neural stem cell self-renewal and neurogenesisJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:06b1ab75-a08e-41b0-a660-3293ca42e838EnglishSymplectic Elements at OxfordPublic Library of Science2009Sansom, SGriffiths, DFaedo, AKleinjan, DRuan, YSmith, JVan Heyningen, VRubenstein, JLivesey, FNeural stem cell self-renewal, neurogenesis, and cell fate determination are processes that control the generation of specific classes of neurons at the correct place and time. The transcription factor Pax6 is essential for neural stem cell proliferation, multipotency, and neurogenesis in many regions of the central nervous system, including the cerebral cortex. We used Pax6 as an entry point to define the cellular networks controlling neural stem cell self-renewal and neurogenesis in stem cells of the developing mouse cerebral cortex. We identified the genomic binding locations of Pax6 in neocortical stem cells during normal development and ascertained the functional significance of genes that we found to be regulated by Pax6, finding that Pax6 positively and directly regulates cohorts of genes that promote neural stem cell self-renewal, basal progenitor cell genesis, and neurogenesis. Notably, we defined a core network regulating neocortical stem cell decision-making in which Pax6 interacts with three other regulators of neurogenesis, Neurog2, Ascl1, and Hes1. Analyses of the biological function of Pax6 in neural stem cells through phenotypic analyses of Pax6 gain- and loss-of-function mutant cortices demonstrated that the Pax6-regulated networks operating in neural stem cells are highly dosage sensitive. Increasing Pax6 levels drives the system towards neurogenesis and basal progenitor cell genesis by increasing expression of a cohort of basal progenitor cell determinants, including the key transcription factor Eomes/Tbr2, and thus towards neurogenesis at the expense of self-renewal. Removing Pax6 reduces cortical stem cell self-renewal by decreasing expression of key cell cycle regulators, resulting in excess early neurogenesis. We find that the relative levels of Pax6, Hes1, and Neurog2 are key determinants of a dynamic network that controls whether neural stem cells self-renew, generate cortical neurons, or generate basal progenitor cells, a mechanism that has marked parallels with the transcriptional control of embryonic stem cell self-renewal. |
| spellingShingle | Sansom, S Griffiths, D Faedo, A Kleinjan, D Ruan, Y Smith, J Van Heyningen, V Rubenstein, J Livesey, F The level of the transcription factor Pax6 is essential for controlling the balance between neural stem cell self-renewal and neurogenesis |
| title | The level of the transcription factor Pax6 is essential for controlling the balance between neural stem cell self-renewal and neurogenesis |
| title_full | The level of the transcription factor Pax6 is essential for controlling the balance between neural stem cell self-renewal and neurogenesis |
| title_fullStr | The level of the transcription factor Pax6 is essential for controlling the balance between neural stem cell self-renewal and neurogenesis |
| title_full_unstemmed | The level of the transcription factor Pax6 is essential for controlling the balance between neural stem cell self-renewal and neurogenesis |
| title_short | The level of the transcription factor Pax6 is essential for controlling the balance between neural stem cell self-renewal and neurogenesis |
| title_sort | level of the transcription factor pax6 is essential for controlling the balance between neural stem cell self renewal and neurogenesis |
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