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Mol Psychiatry. 2018 Feb 21. doi: 10.1038/s41380-018-0025-5. [Epub ahead of print]

Altered TAOK2 activity causes autism-related neurodevelopmental and cognitive abnormalities through RhoA signaling.

Author information

1
Center for Molecular Neurobiology Hamburg (ZMNH), Research Group Neuronal Development, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
2
Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada.
3
Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
4
The Centre for Applied Genomics and Program in Genetics and Genome Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada.
5
Department of Molecular Genetics and McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada.
6
Department of Anatomy and Histology, Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt.
7
Center for Molecular Neurobiology Hamburg (ZMNH), Research Group Behavioral Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
8
Mouse Imaging Center, The Hospital for Sick Children, Toronto, Ontario, Canada.
9
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
10
Developmental Neurophysiology, Institute of Neuroanatomy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
11
Laboratory of Neurobiology, Department of Biosciences, University of Helsinki, Helsinki, Finland.
12
Department of Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
13
Center for Molecular Neurobiology Hamburg (ZMNH), Core Facility Morphology and Electronmicroscopy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
14
The Centre for Applied Genomics and Program in Genetics and Genome Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada. stephen.scherer@sickkids.ca.
15
Department of Molecular Genetics and McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada. stephen.scherer@sickkids.ca.
16
Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada. singhk2@mcmaster.ca.
17
Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada. singhk2@mcmaster.ca.
18
Center for Molecular Neurobiology Hamburg (ZMNH), Research Group Neuronal Development, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. froylan.calderon@zmnh.uni-hamburg.de.

Abstract

Atypical brain connectivity is a major contributor to the pathophysiology of neurodevelopmental disorders (NDDs) including autism spectrum disorders (ASDs). TAOK2 is one of several genes in the 16p11.2 microdeletion region, but whether it contributes to NDDs is unknown. We performed behavioral analysis on Taok2 heterozygous (Het) and knockout (KO) mice and found gene dosage-dependent impairments in cognition, anxiety, and social interaction. Taok2 Het and KO mice also have dosage-dependent abnormalities in brain size and neural connectivity in multiple regions, deficits in cortical layering, dendrite and synapse formation, and reduced excitatory neurotransmission. Whole-genome and -exome sequencing of ASD families identified three de novo mutations in TAOK2 and functional analysis in mice and human cells revealed that all the mutations impair protein stability, but they differentially impact kinase activity, dendrite growth, and spine/synapse development. Mechanistically, loss of Taok2 activity causes a reduction in RhoA activation, and pharmacological enhancement of RhoA activity rescues synaptic phenotypes. Together, these data provide evidence that TAOK2 is a neurodevelopmental disorder risk gene and identify RhoA signaling as a mediator of TAOK2-dependent synaptic development.

PMID:
29467497
DOI:
10.1038/s41380-018-0025-5

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