TAOK2 resides within the 16p11.2 microdeletion/microduplication region; deletions and duplications in this region are strongly associated with neurodevelopmental disorders, including ASD. A de novo loss-of-function (LoF) variant in the TAOK2 gene was identified in an ASD proband from a multiplex family in Yuen et al., 2017, while a second LoF variant in this gene was identified in another ASD proband in Lim et al., 2017. Taok2 heterozygous and knockout mice were found to display gene dosage-dependent impairments in cognition, anxiety, and social interaction, as well as dosage-dependent abnormalities in brain size and neural connectivity in multiple regions, deficits in cortical layering, dendrite and synapse formation, and reducted excitatory neurotransmission (Richter et al., 2018). Richter et al., 2018 also reported TAOK2 genetic variants identified by whole-genome and -exome sequencing of over 2600 families with ASD, including two de novo likely gene-disruptive variants [a missense variant (p.Ala135Pro) that was experimentally shown to display reduced kinase activity and alter dendrite growth and spine/synapse development, as well as a splice-site variant] in simplex families. Scharrenberg et al., 2022 showed that overexpression of TAOK2 with ASD-associated variants disrupted neuronal migration in an isoform-specific manner, neurons lacking Taok2 had unstable microtubules with reduced levels of acetylated tubulin and phosphorylated JNK1, mice lacking Taok2 developed gross cortical and cortex layering abnormalities, and acute Taok2 downregulation or Taok2 knockout delayed the migration of upper-layer cortical neurons in mice.
Molecular Function
This gene encodes a serine/threonine protein kinase that is involved in many different processes, including, cell signaling, microtubule organization and stability, and apoptosis.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder
C57BL6/J Taok2 HT and HM KO mice exhibit abnormal brain morphology, increased brain volume, reduced volume of somatosensory cortex, reduced cerebral cortex, abnormal morphology and size of the corpus callosum, increased ambulation, decreased anxiety, decreased social approach, decreased basal dendrite arborization in the PFC, abnormal spine morphology, decreased synapse number, decreased excitatory neurotransmission, and decreased RhoA activation (Richter M, et al, Mol. Psych., 2018).
References
Type
Title
Author, Year
Primary
Altered TAOK2 activity causes autism-related neurodevelopmental and cognitive abnormalities through RhoA signaling.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Taok2 homozygous knockout mice were generated through Cre mediated deletion of lox P sites within the first and seventh introns of the Taok2 gene. C57BL/6Jtyrc-2Jmice carry a recessive point mutation in the tyrosinase gene resulting in a white coat color, allowing the distinction of targeted cells that confer a black coat color. .
Allele Type: knockout
Strain of Origin: C57BL/6NTac
Genetic Background: C57BL/6 * C57BL/6NTac * SJL
ES Cell Line: Mutant ES Cell Line: PRX-B6N; C57BL/6J^tyrc-2J-derived blastocysts
Model Source: MGI:5554941
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Taok2 heterozygous knockout mice were generated through Cre mediated deletion of lox P sites within the first and seventh introns of the Taok2 gene. C57BL/6Jtyrc-2Jmice carry a recessive point mutation in the tyrosinase gene resulting in a white coat color, allowing the distinction of targeted cells that confer a black coat color. .
Allele Type: knockout
Strain of Origin: C57BL/6NTac
Genetic Background: C57BL/6 * C57BL/6NTac * SJL
ES Cell Line: Mutant ES Cell Line: PRX-B6N; C57BL/6J^tyrc-2J-derived blastocysts
Model Source: MGI:5554941
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
A loxP site was inserted upstream of exon 2. An FRT- and loxP-flanked neomycin resistance cassette was inserted downstream of exon 7. Flp-mediated recombination removed the selection cassette. Cre-mediated recombination removed exons 2 through 7.
Allele Type: Knockout
Strain of Origin: C57BL/6NTac
Genetic Background: C57BL6/J
ES Cell Line: PRX-B6N
Mutant ES Cell Line: Model Source: Kapfhammer
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
A loxP site was inserted upstream of exon 2. An FRT- and loxP-flanked neomycin resistance cassette was inserted downstream of exon 7. Flp-mediated recombination removed the selection cassette. Cre-mediated recombination removed exons 2 through 7.
Allele Type: Knockout
Strain of Origin: C57BL/6NTac
Genetic Background: C57BL6/J
ES Cell Line: PRX-B6N
Mutant ES Cell Line: Model Source: Kapfhammer
Model Type:
Genetic
Model Genotype:
Wildtype
Mutation:
The Taok2 shRNA sequence was inserted into a pSilencer vector. A pSilencer vector containing a random sequence hairpin insert was used as a control for the shRNA. For acute Taok2 downregulation, mouse embryos were electroporated bilaterally in utero. The left hemisphere was electroporated at E15 with Taok2 shRNA and Venus plasmid, while the right hemisphere was electroporated with control shRNA together with mCherry plasmid.
Allele Type: Knockdown
Strain of Origin: Genetic Background: C57BL6/J
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Transgenic
Mutation:
Human-derived mutations in TAOK2 were generated by site-directed mutagenesis. cDNA sequences of wildtype or mutated TAOK2 were re-cloned into a recombinant adeno-associated virus (rAAV)-vector under control of a chicken beta-actin promoter (pCAGIG). TAOK2 mutation construct together with a Venus-expressing plasmid were introduced into cortical progenitor cells by in utero electroporation at E15 to analyze upper-layer neurons.
Allele Type: ASD mutation
Strain of Origin: Genetic Background: C57BL6/J
ES Cell Line: Mutant ES Cell Line: Model Source:
Description: Mutants show the thickness of the ctip2 layer (lower cortical layer) is not changed but the medial and dorsal region of the cortex shows decreases in the thickness of the cux-1-positive layer (upper cortical layer), together with an overall reduced cortex thickness in the dorsal-caudal region, in comparison with controls.
Exp Paradigm: Immunostained for the upper cortex marker cux-1 and the lower cortex marker ctip2 to analyze laminar organization including thickness and density of cortical layers.
Description: Mutant brains show that the number of synapses formed onto the dendrite shaft instead of the postsynaptic spine heads was increased in prefrontal and somatosensory cortical neurons but not in the hippocampus, compared to controls.
Exp Paradigm: NA
Description: Mutants show decreased volume of the somatosensory cortex compared to controls. mutants show decrease in volume of the corpus callosum, many cortical regions, the anterior commissure, and the olfactory bulbs compared to controls.
Exp Paradigm: Volumetric analysis was performed on whole fixed brain tissue.
Dendritic architecture: dendritic tree complexity1
Decreased
Description: Mutants show reduced basal dendrite complexity compared with wt neurons, with only minor reductions in the apical dendrites.
Exp Paradigm: NA
Description: Mutants show no change in the gross organization of cortical layers compared to controls. mutants show cux-1+ cells (upper cortical layer marker) clustered more in the superficial portion of the upper cortical plate, especially in the medial-caudal and dorsal cortex in comparison with controls, upon detailed examination.
Exp Paradigm: Immunostained for the upper cortex marker cux-1 and the lower cortex marker ctip2 to analyze laminar organization including thickness and density of cortical layers.
Description: Mutants show increased coherence within the beta band in comparison to controls, suggesting alterations in hippocampal and prefrontal cortex connectivity, and alterations in long-range functional connectivity, in comparison with controls.
Exp Paradigm: Simultaneous recordings of local field potential (lfp) and multiunit activity were performed from the prelimbic subdivision of the pfc and the ca1 area of the intermediate hippocampus.
Description: Mutants show smaller cortices than wt and taok2 het mice.
Exp Paradigm: Volumetric analysis was performed on whole non-fixed brain tissue.
Description: Mutants show an increase in the number of immature thin and stubby dendritic spines and a decrease in the number of mature mushroom spines compared to controls. mutants show decreased spine length and spine head width compared to controls.
Exp Paradigm: NA
Description: Mutants show increase in total brain volume compared to controls. mutants show increased volume of the hindbrain, midbrain, hypothalamus, thalamus, cerebellum, and hippocampus compared to controls.
Exp Paradigm: Volumetric analysis was performed on whole fixed brain tissue.
Description: Mutant neurons had significant changes in spine distribution and a reduction in the total number of basal dendrite spines per pfc neuron, compared to controls.
Exp Paradigm: NA
Miniature post synaptic current frequency: excitatory1
Decreased
Description: Mutants show reduction in the mean frequency of miniature excitatory postsynaptic currents (mepscs) in the pfc and somatosensory cortex, compared to controls.
Exp Paradigm: NA
Description: Mutants show decreased oscillatory events in the hippocampus in comparison to controls.
Exp Paradigm: Synchrony between oscillatory patterns of electrical activity in the prelimbic subdivision (pl) of the pfc and hc was tested. in vivo extracellular recordings of the lfp and multiple unit activity were conducted in postnatal day p8-10 mice because this is the period of maximal drive from hc to pl and is critical for prelimbic-hippocampal network maturation.
Description: Mutant mice have increased power in discontinuous oscillations in theta (4-12hz), beta (12-30hz) and gamma (30-100hz) frequency ranges in pfc in comparison with controls. mutants show increase in the duration, amplitude, and power in theta (412 hz), beta (1230 hz), and gamma (30100 hz) frequency ranges in comparison with controls.
Exp Paradigm: NA
Description: Mutant mice spent less time sniffing an unfamiliar sex-matched mouse instead of an unfamiliar object and compared with the wt littermates indicating reduced social drive.
Exp Paradigm: An empty beaker or a beaker container an unfamiliar male mouse was placed in a square space.
Description: Mutants spend more time traveling in the open arms of the elevated plus maze in comparison with controls. mutants show no change in the number of entries or time spent in the closed arm or time spent in the center, in comparison to controls.
Exp Paradigm: NA
Description: Mutants show enhanced locomotion only at time points 1530 min compared with wt mice, suggesting that the enhanced locomotion of taok2 ko mice was due to impaired short-term habituation.
Exp Paradigm: NA
Description: Mutant mice performed less alternations than wt mice. reduced alteration do not seem to be caused by increased locomotion as the average transition time between arms did not differ from wt mice and percentage of alternations did not correlate with the average transition time at the individual level.
Exp Paradigm: NA
Description: Mutant mice searched more consistently for the platform at its former position than wt mice as indicated by the reduced mean minimal distance to platform and enhanced time spent at the platform position and platform crossings, compared to controls.
Exp Paradigm: NA
Description: Mutants showed reduced mean minimal distance to the platform during the recall trial of the water maze test compared to controls.
Exp Paradigm: NA
Cued or contextual fear conditioning: memory of context: long term recall1
Decreased
Description: Mutant male mice spent less time immobile compared with wt male littermates, indicating oss of taok2 impairs consolidation or retention of emotional memories specifically in male mice.
Exp Paradigm: NA
Description: Mutants show decreased active gtp-bound rhoa levels in cortical but not hippocampal brain lysates compared with wt. taok2 is minimally expressed in the hippocampus.
Exp Paradigm: NA
Description: Mutants show the thickness of the ctip2 layer (lower cortical layer) is not changed but the medial and dorsal region of the cortex shows decreases in the thickness of the cux-1-positive layer (upper cortical layer), together with an overall reduced cortex thickness in the dorsal-caudal region, in comparison with controls.
Exp Paradigm: Immunostained for the upper cortex marker cux-1 and the lower cortex marker ctip2 to analyze laminar organization including thickness and density of cortical layers.
Description: Mutant neurons had significant changes in spine distribution and a reduction in the total number of basal dendrite spines per pfc neuron, compared to controls.
Exp Paradigm: NA
Description: Mutants show no change in the gross organization of cortical layers compared to controls. mutants show cux-1+ cells (upper cortical layer marker) clustered more in the superficial portion of the upper cortical plate, especially in the medial-caudal and dorsal cortex in comparison with controls, upon detailed examination.
Exp Paradigm: Immunostained for the upper cortex marker cux-1 and the lower cortex marker ctip2 to analyze laminar organization including thickness and density of cortical layers.
Dendritic architecture: dendritic tree complexity1
Decreased
Description: Mutants show reduced basal dendrite complexity compared with wt neurons, with only minor reductions in the apical dendrites.
Exp Paradigm: NA
Description: Mutants show increase in total brain volume compared to controls. mutants show increased volume of the hindbrain, midbrain, hypothalamus, thalamus, cerebellum, and hippocampus compared to controls.
Exp Paradigm: NA
Description: Mutants hsow decreased volume of the somatosensory cortex compared to controls. mutants show decrease in volume of the corpus callosum, many cortical regions, the anterior commissure, and the olfactory bulbs compared to controls.
Exp Paradigm: NA
Description: Mutants show an increase in long thin dendritic spines, a decrease in mushroom spines but no change in stubby spines, compared to controls. mutants show decreased spine length and spine head width compared to controls. mutants show no change in spine morphology in the hippocampus compared to controls.
Exp Paradigm: NA
Miniature post synaptic current frequency: excitatory1
Decreased
Description: Mutants show reduction in the mean frequency of miniature excitatory postsynaptic currents (mepscs) in the pfc compared to controls.
Exp Paradigm: NA
Cued or contextual fear conditioning: memory of context: long term recall1
Decreased
Description: Mutant male mice spent less time immobile compared with wt male littermates, indicating oss of taok2 impairs consolidation or retention of emotional memories specifically in male mice.
Exp Paradigm: NA
Description: A longitudinal study using magnetic resonance imaging (MRI) revealed that the cortex of Taok2 knockout mice shows a significant reduction in volume throughout development concomitant with a higher cortex curvature, from early postnatal development until adulthood.
Description: Venus-labeled neurons in the knockout cortices showed a more superficial position at P21 compared with wildtype littermates.
Exp Paradigm: Venus
Description: Taok2 knockout mice displayed decreased cortical plate thickness compared to wildtype littermates. However, there were no differences in the thickness of either the ventricular zone or intermediate zone in Taok2 knockout mice.
Description: Taok2-deficient cells exhibited a significant decrease in migration speed after acute downregulation of Taok2compared with wildtype cortices.
Exp Paradigm: Venus
Description: In Taok2 knockout mouse cortices at E19, migrating neurons were held back at the intermediate zone, whereas wildtype neurons were able to reach the cortical plate. No differences in the ventricular zone or intermediate zone were observed at E18.
Exp Paradigm: Venus
Description: In Taok2 heterozygous mouse cortices at E19, migrating neurons were held back at the intermediate zone, whereas wildtype neurons were able to reach the cortical plate. No differences in the ventricular zone or intermediate zone were observed at E18.
Exp Paradigm: Venus
Description: A longitudinal study using magnetic resonance imaging (MRI) revealed that the cortex of Taok2 heterozygous mice shows a significant reduction in volume throughout development concomitant with a higher cortex curvature, from early postnatal development until adulthood.
Description: Taok2-deficient cells exhibited a significant decrease in migration speed in labeled neurons in Het cortices compared with wildtype cortices.
Exp Paradigm: Venus
Description: In the Taok2 knockdown model, through expression of Taok2 shRNA in postmitotic cells, there was a change in the distribution of transfected cells in the developing cortex, with more cells in the intermediate zone and fewer in the cortical plate than in control-transfected cortices.
Exp Paradigm: GFP
Description: There was a greater proportion of round cells present after Taok2 downregulation compared with control-transfected cells at E18. However, this effect was no longer detectable at E19. The ratio of length/width was significantly decreased in Taok2 shRNA cells at E18 compared with control cells but not at E19. In addition, the leading process width was significantly thinner in Taok2 shRNA cells at E19 compared with control-transfected cells.
Exp Paradigm: Venus
Description: In mouse cortices after Taok2 downregulation at E19, migrating neurons were held back at the intermediate zone, whereas control neurons were able to reach the cortical plate. No differences in the ventricular zone or intermediate zone were observed at E18.
Exp Paradigm: Venus
Description: Taok2-deficient cells exhibited a significant decrease in migration speed after acute downregulation of Taok2 compared with control cortices.
Exp Paradigm: Venus
Description: Taok2 shRNA-transfected neurons reached a higher position toward the pia than the control-transfected cells on the contralateral side. Populations of Taok2-downregulated neurons and contralateral control-transfected neurons both expressed Cux-1, thus, Taok2 deficiency does not affect layer identity.
Exp Paradigm: Venus
Description: The rate of cells transfected with TAOK2alphaA135P and TAOK2alphaA335V in the intermediate zone increased compared with that of control-transfected cortices or cells expressing TAOK2alphaWT.
Exp Paradigm: Venus
