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. Author manuscript; available in PMC: 2019 Jul 7.
Published in final edited form as: Nat Neurosci. 2019 Jan 7;22(2):243–255. doi: 10.1038/s41593-018-0295-x

Figure 7: Bypassing the NSC state restores early neurodevelopmental aberrations.

Figure 7:

a, A significant enrichment of PSA-NCAM+ cells was present in ASD NSC-derived neurons (NSC-N) at 4 dpi as compared to their respective controls (**P=0.0016, Mann-Whitney U-test), whereas no difference was observed in iPSC-iNs (P=0.805, Mann-Whitney U-test, not significant). Box plots show median (center line), mean (‘+’) and interquartile range (IQR), with whiskers representing the minimum and maximum of data points; ASD: n=8 biologically independent patient lines (42 technical replicates total), control n=5 biologically independent patient lines (22 technical replicates total). b, Sholl analysis of subtle branching patterns in patient-derived iPSC-iNs at 14 days post conversion. Values represent mean ± s.e.m.; ASD: n=8 biologically independent patient lines, control: n=5 biologically independent patient lines. c, Left: Total neurite growth assessment of converting iPSC-iNs. Values represent mean ± s.d.; ASD: n=8 biologically independent patient lines (482 tracing replicates total), control: n=5 biologically independent patient lines (264 tracing replicates total). Right: ASD NSC-Ns had significantly longer neurites at 14 dpi as compared with their respective controls (control NSC-N: 421.8 ± 14.14 μm, ASD NSC-N: 552.32 ± 24.86 μm, **P=0.0062, Mann-Whitney U-test), whereas no difference was observed in iPSC-iPSC-iNs at 14 days post conversion (control iPSC-INs: 442.39 ± 23.93 μm, ASD iPSC-iNs: 439.07 ± 14.51 μm, P=0.9433, Mann-Whitney U-test, not significant). Values represent mean ± s.e.m.; ASD: n=8 biologically independent patient lines, control: n=5 biologically independent patient lines. d, WGCNA cluster dendrogram of all 52 iPSC-iN time series samples groups genes into distinct modules (top row). The middle row shows strong differential expression relationships for developmental time (days of iPSC-iN conversion). TM1 genes (bottom row; Fig. 2) show high module preservation in the iPSC-iN gene network (also see Extended Data Fig. 10c-e). e, Density plot showing the temporal ME alignment for the TM1-equivalent iPSC-iN module blue between control (reference) and ASD (query) during iPSC-iN maturation. The average cost per step is displayed as a density distribution with contours superimposed. f, GS values of the top 60 TM1 hub genes for ASD and control individuals in NSC-derived neurons (left) or when bypassing the NSC stage (iPSC-iN technology, right) after 14 days. Violin plots show median (center line), IQR (box), 95% confidence interval and the kernel probability density at different values; n=60 genes. Also see Extended Data Figures 8, 9 and 10.