Journal article
Incorrect dosage of IQSEC2, a known intellectual disability and epilepsy gene, disrupts dendritic spine morphogenesis
Translational Psychiatry, Vol.7, e1110
2017
Abstract
There is considerable genetic and phenotypic heterogeneity associated with intellectual disability (ID), specific learning disabilities, attention-deficit hyperactivity disorder, autism and epilepsy. The intelligence quotient (IQ) motif and SEC7 domain containing protein 2 gene (IQSEC2) is located on the X-chromosome and harbors mutations that contribute to non-syndromic ID with and without early-onset seizure phenotypes in both sexes. Although IQ and Sec7 domain mutations lead to partial loss of IQSEC2 enzymatic activity, the in vivo pathogenesis resulting from these mutations is not known. Here we reveal that IQSEC2 has a key role in dendritic spine morphology. Partial loss-of-function mutations were modeled using a lentiviral short hairpin RNA (shRNA) approach, which achieved a 57% knockdown of Iqsec2 expression in primary hippocampal cell cultures from mice. Investigating gross morphological parameters after 8 days of in vitro culture (8DIV) identified a 32% reduction in primary axon length, in contrast to a 27% and 31% increase in the number and complexity of dendrites protruding from the cell body, respectively. This increase in dendritic complexity and spread was carried through dendritic spine development, with a 34% increase in the number of protrusions per dendritic segment compared with controls at 15DIV. Although the number of dendritic spines had normalized by 21DIV, a reduction was noted in the number of immature spines. In contrast, when modeling increased dosage, overexpression of wild-type IQSEC2 led to neurons with shorter axons that were more compact and displayed simpler dendritic branching. Disturbances to dendritic morphology due to knockdown of Iqsec2 were recapitulated in neurons from Iqsec2 knockout mice generated in our laboratory using CRISPR/Cas9 technology. These observations provide evidence of dosage sensitivity for IQSEC2, which normally escapes X-inactivation in females, and links these disturbances in expression to alterations in the morphology of developing neurons.
Details
- Title
- Incorrect dosage of IQSEC2, a known intellectual disability and epilepsy gene, disrupts dendritic spine morphogenesis
- Authors
- S J Hinze (Author) - University of AdelaideMatilda R Jackson (Author) - University of AdelaideS Lie (Author) - University of AdelaideL Jolly (Author) - University of AdelaideM Field (Author) - The Genetic of Learning Disability Service, Waratah NSWS C Barry (Author) - University of AdelaideRobert J Harvey (Author) - University College London, United KingdomC Shoubridge (Author) - University of Adelaide
- Publication details
- Translational Psychiatry, Vol.7, e1110; 11
- Publisher
- Nature Publishing Group
- Date published
- 2017
- DOI
- 10.1038/tp.2017.81
- ISSN
- 2158-3188
- Copyright note
- Copyright © 2017 The Authors. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if thematerial is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
- Organisation Unit
- School of Health; University of the Sunshine Coast, Queensland; School of Health and Sport Sciences - Legacy; Centre for Bioinnovation; School of Health and Behavioural Sciences - Legacy
- Language
- English
- Record Identifier
- 99451153702621
- Output Type
- Journal article
Metrics
14 File views/ downloads
284 Record Views
InCites Highlights
These are selected metrics from InCites Benchmarking & Analytics tool, related to this output
- Collaboration types
- Domestic collaboration
- International collaboration
- Web Of Science research areas
- Psychiatry