Mob2 Insufficiency Disrupts Neuronal Migration in the Developing Cortex
Disorders of neuronal mispositioning during brain development are phenotypically heterogeneous and their genetic causes remain largely unknown. Here, we report biallelic variants in a Hippo signaling factor—MOB2—in a patient with one such disorder, periventricular nodular heterotopia (PH). Genetic a...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-03-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fncel.2018.00057/full |
| _version_ | 1828498082590883840 |
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| author | Adam C. O’Neill Adam C. O’Neill Christina Kyrousi Melanie Einsiedler Ingo Burtscher Ingo Burtscher Micha Drukker Micha Drukker David M. Markie Edwin P. Kirk Magdalena Götz Magdalena Götz Magdalena Götz Stephen P. Robertson Silvia Cappello |
| author_facet | Adam C. O’Neill Adam C. O’Neill Christina Kyrousi Melanie Einsiedler Ingo Burtscher Ingo Burtscher Micha Drukker Micha Drukker David M. Markie Edwin P. Kirk Magdalena Götz Magdalena Götz Magdalena Götz Stephen P. Robertson Silvia Cappello |
| author_sort | Adam C. O’Neill |
| collection | DOAJ |
| description | Disorders of neuronal mispositioning during brain development are phenotypically heterogeneous and their genetic causes remain largely unknown. Here, we report biallelic variants in a Hippo signaling factor—MOB2—in a patient with one such disorder, periventricular nodular heterotopia (PH). Genetic and cellular analysis of both variants confirmed them to be loss-of-function with enhanced sensitivity to transcript degradation via nonsense mediated decay (NMD) or increased protein turnover via the proteasome. Knockdown of Mob2 within the developing mouse cortex demonstrated its role in neuronal positioning. Cilia positioning and number within migrating neurons was also impaired with comparable defects detected following a reduction in levels of an upstream modulator of Mob2 function, Dchs1, a previously identified locus associated with PH. Moreover, reduced Mob2 expression increased phosphorylation of Filamin A, an actin cross-linking protein frequently mutated in cases of this disorder. These results reveal a key role for Mob2 in correct neuronal positioning within the developing cortex and outline a new candidate locus for PH development. |
| first_indexed | 2024-12-11T12:59:14Z |
| format | Article |
| id | doaj.art-55a80b0d7f3942dc8de72836ea5c1499 |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-12-11T12:59:14Z |
| publishDate | 2018-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-55a80b0d7f3942dc8de72836ea5c14992022-12-22T01:06:30ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022018-03-011210.3389/fncel.2018.00057336394Mob2 Insufficiency Disrupts Neuronal Migration in the Developing CortexAdam C. O’Neill0Adam C. O’Neill1Christina Kyrousi2Melanie Einsiedler3Ingo Burtscher4Ingo Burtscher5Micha Drukker6Micha Drukker7David M. Markie8Edwin P. Kirk9Magdalena Götz10Magdalena Götz11Magdalena Götz12Stephen P. Robertson13Silvia Cappello14Department of Women’s and Children’s Health, University of Otago, Dunedin, New ZealandHelmholtz Center, Institute of Stem Cell Research, Munich, GermanyMax Planck Institute of Psychiatry, Munich, GermanyHelmholtz Center, Institute of Stem Cell Research, Munich, GermanyHelmholtz Center, Institute of Stem Cell Research, Munich, GermanyHelmholtz Center Munich, Institute of Diabetes and Regeneration Research, Garching, GermanyHelmholtz Center, Institute of Stem Cell Research, Munich, GermanyHelmholtz Center, iPSC Core Facility, Munich, GermanyDepartment of Pathology, University of Otago, Dunedin, New ZealandSydney Children’s Hospital, University of New South Wales and New South Wales Health Pathology, Randwick, NSW, AustraliaHelmholtz Center, Institute of Stem Cell Research, Munich, GermanyPhysiological Genomics, Biomedical Center, Ludwig-Maximilians-University, Munich, GermanyExcellence Cluster of Systems Neurology (SYNERGY), Munich, GermanyDepartment of Women’s and Children’s Health, University of Otago, Dunedin, New ZealandMax Planck Institute of Psychiatry, Munich, GermanyDisorders of neuronal mispositioning during brain development are phenotypically heterogeneous and their genetic causes remain largely unknown. Here, we report biallelic variants in a Hippo signaling factor—MOB2—in a patient with one such disorder, periventricular nodular heterotopia (PH). Genetic and cellular analysis of both variants confirmed them to be loss-of-function with enhanced sensitivity to transcript degradation via nonsense mediated decay (NMD) or increased protein turnover via the proteasome. Knockdown of Mob2 within the developing mouse cortex demonstrated its role in neuronal positioning. Cilia positioning and number within migrating neurons was also impaired with comparable defects detected following a reduction in levels of an upstream modulator of Mob2 function, Dchs1, a previously identified locus associated with PH. Moreover, reduced Mob2 expression increased phosphorylation of Filamin A, an actin cross-linking protein frequently mutated in cases of this disorder. These results reveal a key role for Mob2 in correct neuronal positioning within the developing cortex and outline a new candidate locus for PH development.http://journal.frontiersin.org/article/10.3389/fncel.2018.00057/fullMob2Hippo pathwayperiventricular heterotopiacortical developmentexome sequencing |
| spellingShingle | Adam C. O’Neill Adam C. O’Neill Christina Kyrousi Melanie Einsiedler Ingo Burtscher Ingo Burtscher Micha Drukker Micha Drukker David M. Markie Edwin P. Kirk Magdalena Götz Magdalena Götz Magdalena Götz Stephen P. Robertson Silvia Cappello Mob2 Insufficiency Disrupts Neuronal Migration in the Developing Cortex Frontiers in Cellular Neuroscience Mob2 Hippo pathway periventricular heterotopia cortical development exome sequencing |
| title | Mob2 Insufficiency Disrupts Neuronal Migration in the Developing Cortex |
| title_full | Mob2 Insufficiency Disrupts Neuronal Migration in the Developing Cortex |
| title_fullStr | Mob2 Insufficiency Disrupts Neuronal Migration in the Developing Cortex |
| title_full_unstemmed | Mob2 Insufficiency Disrupts Neuronal Migration in the Developing Cortex |
| title_short | Mob2 Insufficiency Disrupts Neuronal Migration in the Developing Cortex |
| title_sort | mob2 insufficiency disrupts neuronal migration in the developing cortex |
| topic | Mob2 Hippo pathway periventricular heterotopia cortical development exome sequencing |
| url | http://journal.frontiersin.org/article/10.3389/fncel.2018.00057/full |
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