Foxc1 dependent mesenchymal signalling drives embryonic cerebellar growth
Loss of Foxc1 is associated with Dandy-Walker malformation, the most common human cerebellar malformation characterized by cerebellar hypoplasia and an enlarged posterior fossa and fourth ventricle. Although expressed in the mouse posterior fossa mesenchyme, loss of Foxc1 non-autonomously induces a...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2014-12-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/03962 |
| _version_ | 1811253139463995392 |
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| author | Parthiv Haldipur Gwendolyn S Gillies Olivia K Janson Victor V Chizhikov Divakar S Mithal Richard J Miller Kathleen J Millen |
| author_facet | Parthiv Haldipur Gwendolyn S Gillies Olivia K Janson Victor V Chizhikov Divakar S Mithal Richard J Miller Kathleen J Millen |
| author_sort | Parthiv Haldipur |
| collection | DOAJ |
| description | Loss of Foxc1 is associated with Dandy-Walker malformation, the most common human cerebellar malformation characterized by cerebellar hypoplasia and an enlarged posterior fossa and fourth ventricle. Although expressed in the mouse posterior fossa mesenchyme, loss of Foxc1 non-autonomously induces a rapid and devastating decrease in embryonic cerebellar ventricular zone radial glial proliferation and concurrent increase in cerebellar neuronal differentiation. Subsequent migration of cerebellar neurons is disrupted, associated with disordered radial glial morphology. In vitro, SDF1α, a direct Foxc1 target also expressed in the head mesenchyme, acts as a cerebellar radial glial mitogen and a chemoattractant for nascent Purkinje cells. Its receptor, Cxcr4, is expressed in cerebellar radial glial cells and conditional Cxcr4 ablation with Nes-Cre mimics the Foxc1−/− cerebellar phenotype. SDF1α also rescues the Foxc1−/− phenotype. Our data emphasizes that the head mesenchyme exerts a considerable influence on early embryonic brain development and its disruption contributes to neurodevelopmental disorders in humans. |
| first_indexed | 2024-04-12T16:46:09Z |
| format | Article |
| id | doaj.art-6dc0ae03148e442297b9205442a87a09 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:46:09Z |
| publishDate | 2014-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-6dc0ae03148e442297b9205442a87a092022-12-22T03:24:34ZengeLife Sciences Publications LtdeLife2050-084X2014-12-01310.7554/eLife.03962Foxc1 dependent mesenchymal signalling drives embryonic cerebellar growthParthiv Haldipur0Gwendolyn S Gillies1Olivia K Janson2Victor V Chizhikov3Divakar S Mithal4Richard J Miller5Kathleen J Millen6Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United StatesCenter for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United StatesCenter for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United StatesDepartment of Anatomy and Neurobiology, University of Tennessee Health Sciences Center, Memphis, United StatesDepartment of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, United StatesDepartment of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, United StatesCenter for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States; Department of Pediatrics, Genetics Division, University of Washington, Seattle, United StatesLoss of Foxc1 is associated with Dandy-Walker malformation, the most common human cerebellar malformation characterized by cerebellar hypoplasia and an enlarged posterior fossa and fourth ventricle. Although expressed in the mouse posterior fossa mesenchyme, loss of Foxc1 non-autonomously induces a rapid and devastating decrease in embryonic cerebellar ventricular zone radial glial proliferation and concurrent increase in cerebellar neuronal differentiation. Subsequent migration of cerebellar neurons is disrupted, associated with disordered radial glial morphology. In vitro, SDF1α, a direct Foxc1 target also expressed in the head mesenchyme, acts as a cerebellar radial glial mitogen and a chemoattractant for nascent Purkinje cells. Its receptor, Cxcr4, is expressed in cerebellar radial glial cells and conditional Cxcr4 ablation with Nes-Cre mimics the Foxc1−/− cerebellar phenotype. SDF1α also rescues the Foxc1−/− phenotype. Our data emphasizes that the head mesenchyme exerts a considerable influence on early embryonic brain development and its disruption contributes to neurodevelopmental disorders in humans.https://elifesciences.org/articles/03962neurodevelopmental disorderradial gliacerebellumCxcl12foxc1 |
| spellingShingle | Parthiv Haldipur Gwendolyn S Gillies Olivia K Janson Victor V Chizhikov Divakar S Mithal Richard J Miller Kathleen J Millen Foxc1 dependent mesenchymal signalling drives embryonic cerebellar growth eLife neurodevelopmental disorder radial glia cerebellum Cxcl12 foxc1 |
| title | Foxc1 dependent mesenchymal signalling drives embryonic cerebellar growth |
| title_full | Foxc1 dependent mesenchymal signalling drives embryonic cerebellar growth |
| title_fullStr | Foxc1 dependent mesenchymal signalling drives embryonic cerebellar growth |
| title_full_unstemmed | Foxc1 dependent mesenchymal signalling drives embryonic cerebellar growth |
| title_short | Foxc1 dependent mesenchymal signalling drives embryonic cerebellar growth |
| title_sort | foxc1 dependent mesenchymal signalling drives embryonic cerebellar growth |
| topic | neurodevelopmental disorder radial glia cerebellum Cxcl12 foxc1 |
| url | https://elifesciences.org/articles/03962 |
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