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O'Neill, A.C. ; Kyrousi, C.* ; Einsiedler, M. ; Burtscher, I. ; Drukker, M. ; Markie, D.M.* ; Kirk, E.P.* ; Götz, M. ; Robertson, S.P.* ; Cappello, S.*

Mob2 insufficiency disrupts neuronal migration in the developing cortex.

Front. Cell. Neurosci. 12:57 (2018)
Publ. Version/Full Text Research data DOI PMC
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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--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 ofwithin 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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Hippo Pathway ; Mob2 ; Cortical Development ; Exome Sequencing ; Periventricular Heterotopia; Periventricular Nodular Heterotopia; Hippo Signaling Pathway; Human Ndr Kinases; Cortical Development; Cerebral-cortex; Human Brain; In-vivo; Mutations; Receptor; Genes
Language english
Publication Year 2018
HGF-reported in Year 2018
e-ISSN 1662-5102
Journal Frontiers in Cellular Neuroscience
Quellenangaben Volume: 12, Issue: , Pages: , Article Number: 57 Supplement: ,
Publisher Frontiers
Publishing Place Lausanne
Reviewing status Peer reviewed
Institute(s) Institute of Stem Cell Research (ISF)
Institute of Diabetes and Regeneration Research (IDR)
POF-Topic(s) 30204 - Cell Programming and Repair
30201 - Metabolic Health
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Research field(s) Stem Cell and Neuroscience
Helmholtz Diabetes Center
PSP Element(s) G-500800-001
G-502300-001
G-552400-001
DOI 10.3389/fncel.2018.00057
WOS ID WOS:000427201400001
Scopus ID 85046648731
PubMed ID 29593499
Erfassungsdatum 2018-05-25
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