Fig. 8: TAOK2 ameliorates neuronal migration deficits in the 16p11.2 microdeletion mouse model.

a Loss of the ASD susceptibility gene locus 16p11.2 disrupts neuronal migration in the developing cortex with cells arrested in the IZ. b Quantification of cell distribution in the 16p11.2 deletion model (****p < 0.0001 by unpaired t-test; WT = 3 brains, 16p11.2 del Het = 4 brains; median is represented by red line; see Supplementary Fig. 12a for individual brains). c Time-lapse analysis of migrating neurons in the CP of WT and Het 16p11.2 deletion mice. Right panel: three stacks superimposed (each color represents a different time point) show reduced neuronal migration in 16p11.2 deletion mice. d Quantification of neuronal migration speed in the developing cortex in 16p11.2 deletion mice (**p = 0.0048 by unpaired t-test; WT = 30 cells, 16p11.2 del Het = 30 cells from slices of at least 3 brains per condition; values are the mean ± s.e.m.). e TAOK2αWT but not TAOK2αA135P rescues neuronal migration deficits in the Het 16p11.2 microdeletion mouse model. f Quantification of cell distribution in the developing cortex shows a shift of neurons from the IZ toward the UCP after TAOK2αWT expression compared with Het 16p11.2 cortices expressing only Venus or TAOK2αA135P (p < 0.0001 by one-way ANOVA, post hoc Dunnett’s multiple test ****p < 0.0001; 16p11.2 del Het = 4 brains, 16p11.2 del Het + TAOK2αWT = 6 brains, 16p11.2 del Het + TAOK2αA135P = 3 brains; see Supplementary Fig. 12a for individual brains; median is represented by red line). g Kymographs of EB3-GFP signals along neurites from WT (upper left panels) and Het 16p11.2 del cells (upper right panels) in dissociated cultures. Kymograph analysis shows an overall change in the trajectories of EB3 comets (green lines) with steeper trajectories in the Het 16p11.2 deletion. Ectopic expression of TAOK2α (lower left panels) and MKK7-JNK1 (lower right panels) ameliorates increased microtubule dynamics in Het 16p11.2 del cells. h Left graph: quantification of EB3 speed in the neurite shaft in dissociated cells. Het 16p11.2 del cells show an increased EB3 speed that is restored after TAOK2α and MKK7-JNK1 expression. Right graph: all values for EB3 speed from the individual cells. (p < 0.0001 by one-way ANOVA, post hoc Dunnett’s multiple test ****p < 0.0001; n = 15 cells from three different cultures for each condition; values are the mean ± s.e.m.). Scale bar: 200 μm.