A Primate-Specific Isoform of PLEKHG6 Regulates Neurogenesis and Neuronal Migration
Summary: The mammalian neocortex has undergone remarkable changes through evolution. A consequence of such rapid evolutionary events could be a trade-off that has rendered the brain susceptible to certain neurodevelopmental and neuropsychiatric conditions. We analyzed the exomes of 65 patients with...
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2018-12-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124718317753 |
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doaj-d95a7e66dd6f4400b94ec2e97ad2e7b32020-11-24T22:14:29ZengElsevierCell Reports2211-12472018-12-01251027292741.e6A Primate-Specific Isoform of PLEKHG6 Regulates Neurogenesis and Neuronal MigrationAdam C. O’Neill0Christina Kyrousi1Johannes Klaus2Richard J. Leventer3Edwin P. Kirk4Andrew Fry5Daniela T. Pilz6Tim Morgan7Zandra A. Jenkins8Micha Drukker9Samuel F. Berkovic10Ingrid E. Scheffer11Renzo Guerrini12David M. Markie13Magdalena Götz14Silvia Cappello15Stephen P. Robertson16Department of Women’s and Children’s Health, University of Otago, Dunedin, New Zealand; Institute of Stem Cell Research, Helmholtz Center, Munich, Germany; Physiological Genomics, Biomedical Center Ludwig-Maximilians-Universitaet, Munich, GermanyMax Planck Institute of Psychiatry, Munich, GermanyMax Planck Institute of Psychiatry, Munich, GermanyDepartment of Neurology, Murdoch Children’s Research Institute, Parkville, VIC, Australia; Department of Paediatrics, University of Melbourne, Parkville, VIC, AustraliaSydney Children’s Hospital, University of New South Wales, Randwick, NSW, Australia; New South Wales Health Pathology, Randwick, NSW, AustraliaInstitute of Medical Genetics, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, UKWest of Scotland Genetics Service, Laboratory Medicine Building, Queen Elizabeth University Hospital, Glasgow G51 4TF, UKDepartment of Women’s and Children’s Health, University of Otago, Dunedin, New ZealandDepartment of Women’s and Children’s Health, University of Otago, Dunedin, New ZealandInstitute of Stem Cell Research, Helmholtz Center, Munich, GermanyEpilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC 3084, AustraliaEpilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia; The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, AustraliaPediatric Neurology Unit and Laboratories, Children’s Hospital A. Meyer-University of Florence, Florence, ItalyDepartment of Pathology, University of Otago, Dunedin, New ZealandInstitute of Stem Cell Research, Helmholtz Center, Munich, Germany; Physiological Genomics, Biomedical Center Ludwig-Maximilians-Universitaet, Munich, Germany; Excellence Cluster of Systems Neurology (SYNERGY), 82152 Planegg/Martinsried, GermanyMax Planck Institute of Psychiatry, Munich, Germany; Corresponding authorDepartment of Women’s and Children’s Health, University of Otago, Dunedin, New Zealand; Corresponding authorSummary: The mammalian neocortex has undergone remarkable changes through evolution. A consequence of such rapid evolutionary events could be a trade-off that has rendered the brain susceptible to certain neurodevelopmental and neuropsychiatric conditions. We analyzed the exomes of 65 patients with the structural brain malformation periventricular nodular heterotopia (PH). De novo coding variants were observed in excess in genes defining a transcriptomic signature of basal radial glia, a cell type linked to brain evolution. In addition, we located two variants in human isoforms of two genes that have no ortholog in mice. Modulating the levels of one of these isoforms for the gene PLEKHG6 demonstrated its role in regulating neuroprogenitor differentiation and neuronal migration via RhoA, with phenotypic recapitulation of PH in human cerebral organoids. This suggests that this PLEKHG6 isoform is an example of a primate-specific genomic element supporting brain development. : O’Neill et al. show that variants in patients with PH are enriched within genes that define basal radial glia transcriptomic signatures and provide mechanistic evidence that a primate-specific isoform of one gene, mutated in a patient with PH, regulates neurogenesis. Keywords: cortical development, evolution, periventricular heterotopia, PLEKHG6, MyoGEF, RhoAhttp://www.sciencedirect.com/science/article/pii/S2211124718317753 |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Adam C. O’Neill Christina Kyrousi Johannes Klaus Richard J. Leventer Edwin P. Kirk Andrew Fry Daniela T. Pilz Tim Morgan Zandra A. Jenkins Micha Drukker Samuel F. Berkovic Ingrid E. Scheffer Renzo Guerrini David M. Markie Magdalena Götz Silvia Cappello Stephen P. Robertson |
| spellingShingle |
Adam C. O’Neill Christina Kyrousi Johannes Klaus Richard J. Leventer Edwin P. Kirk Andrew Fry Daniela T. Pilz Tim Morgan Zandra A. Jenkins Micha Drukker Samuel F. Berkovic Ingrid E. Scheffer Renzo Guerrini David M. Markie Magdalena Götz Silvia Cappello Stephen P. Robertson A Primate-Specific Isoform of PLEKHG6 Regulates Neurogenesis and Neuronal Migration Cell Reports |
| author_facet |
Adam C. O’Neill Christina Kyrousi Johannes Klaus Richard J. Leventer Edwin P. Kirk Andrew Fry Daniela T. Pilz Tim Morgan Zandra A. Jenkins Micha Drukker Samuel F. Berkovic Ingrid E. Scheffer Renzo Guerrini David M. Markie Magdalena Götz Silvia Cappello Stephen P. Robertson |
| author_sort |
Adam C. O’Neill |
| title |
A Primate-Specific Isoform of PLEKHG6 Regulates Neurogenesis and Neuronal Migration |
| title_short |
A Primate-Specific Isoform of PLEKHG6 Regulates Neurogenesis and Neuronal Migration |
| title_full |
A Primate-Specific Isoform of PLEKHG6 Regulates Neurogenesis and Neuronal Migration |
| title_fullStr |
A Primate-Specific Isoform of PLEKHG6 Regulates Neurogenesis and Neuronal Migration |
| title_full_unstemmed |
A Primate-Specific Isoform of PLEKHG6 Regulates Neurogenesis and Neuronal Migration |
| title_sort |
primate-specific isoform of plekhg6 regulates neurogenesis and neuronal migration |
| publisher |
Elsevier |
| series |
Cell Reports |
| issn |
2211-1247 |
| publishDate |
2018-12-01 |
| description |
Summary: The mammalian neocortex has undergone remarkable changes through evolution. A consequence of such rapid evolutionary events could be a trade-off that has rendered the brain susceptible to certain neurodevelopmental and neuropsychiatric conditions. We analyzed the exomes of 65 patients with the structural brain malformation periventricular nodular heterotopia (PH). De novo coding variants were observed in excess in genes defining a transcriptomic signature of basal radial glia, a cell type linked to brain evolution. In addition, we located two variants in human isoforms of two genes that have no ortholog in mice. Modulating the levels of one of these isoforms for the gene PLEKHG6 demonstrated its role in regulating neuroprogenitor differentiation and neuronal migration via RhoA, with phenotypic recapitulation of PH in human cerebral organoids. This suggests that this PLEKHG6 isoform is an example of a primate-specific genomic element supporting brain development. : O’Neill et al. show that variants in patients with PH are enriched within genes that define basal radial glia transcriptomic signatures and provide mechanistic evidence that a primate-specific isoform of one gene, mutated in a patient with PH, regulates neurogenesis. Keywords: cortical development, evolution, periventricular heterotopia, PLEKHG6, MyoGEF, RhoA |
| url |
http://www.sciencedirect.com/science/article/pii/S2211124718317753 |
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