Abstract
Mid-hindbrain malformations can occur during embryogenesis through a disturbance of transient and localized gene expression patterns within these distinct brain structures. Rho guanine nucleotide exchange factor (ARHGEF) family members are key for controlling the spatiotemporal activation of Rho GTPase, to modulate cytoskeleton dynamics, cell division, and cell migration. We identified, by means of whole exome sequencing, a homozygous frameshift mutation in the ARHGEF2 as a cause of intellectual disability, a midbrain-hindbrain malformation, and mild microcephaly in a consanguineous pedigree of Kurdish-Turkish descent. We show that loss of ARHGEF2 perturbs progenitor cell differentiation and that this is associated with a shift of mitotic spindle plane orientation, putatively favoring more symmetric divisions. The ARHGEF2 mutation leads to reduction in the activation of the RhoA/ROCK/MLC pathway crucial for cell migration. We demonstrate that the human brain malformation is recapitulated in Arhgef2 mutant mice and identify an aberrant migration of distinct components of the precerebellar system as a pathomechanism underlying the midbrain-hindbrain phenotype. Our results highlight the crucial function of ARHGEF2 in human brain development and identify a mutation in ARHGEF2 as novel cause of a neurodevelopmental disorder.
Highlights
Brain development depends on spatiotemporally controlled gene expression.[1,2,3] Alterations in the expression pattern of such genes can result in neurodevelopmental disorders by impinging on key processes such as neural progenitor specification, cell division, and differentiation and the migration of newly born neurons from their site of origin to their final destination within the brain.[4,5,6] The latter is crucial for the formation of specific brain structures.[7,8,9] Factors that control localized gene function include Rho GTPase regulators
During brain development, localized gene expression is crucial for the formation and function of specific brain regions
We identified a frameshift mutation in the Rho guanine nucleotide exchange factor 2 gene (ARHGEF2) in two children presenting with intellectual disability, mild microcephaly, and a midbrain-hindbrain malformation
Summary
Brain development depends on spatiotemporally controlled gene expression.[1,2,3] Alterations in the expression pattern of such genes can result in neurodevelopmental disorders by impinging on key processes such as neural progenitor specification, cell division, and differentiation and the migration of newly born neurons from their site of origin to their final destination within the brain.[4,5,6] The latter is crucial for the formation of specific brain structures.[7,8,9] Factors that control localized gene function include Rho GTPase regulators. Arhgef participates in the migration of non-neuronal cells and in Wnt-induced planar cell polarity, via the activation of RhoA.[28, 29] evidence for a central function of Arhgef in cytoskeletal dynamics and critical signal transduction pathways exists and other ARHGEF genes have been linked with neurological disease,[30,31,32] little is known about ARHGEF2 function in humans and no disease phenotype associated with this gene has been reported
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
