TAOK2 drives opposing cilia length deficits in 16p11.2 deletion and duplication carriers

Deletion and duplication of the 16p11.2 genomic locus are associated with opposing changes in brain size. To determine cellular mechanisms that underlie these opposing phenotypes, we performed quantitative phosphoproteomic analyses of induced pluripotent stem cells (iPSCs)-derived neural progenitor cells (NPCs) obtained from unaffected individuals, 16p11.2 deletion, and 16p11.2 duplication carriers. Differentially phosphorylated proteins were enriched in centrosomal and cilia proteins. Deletion NPCs showed longer primary cilium compared to unaffected individuals, while stunted cilia were observed in duplication NPCs. Through cellular screens in NPCs, we determined the contribution of genes within the 16p11.2 locus to cilium length. Protein kinase TAOK2 and phosphatase PPP4C were found to regulate primary cilia length. NPCs lacking TAOK2 exhibited elongated cilia, aberrant IFT88 and pericentrin (PCNT) accumulation, and were impaired in sonic hedgehog (SHH) signaling. These findings implicate aberrant cilia length in the pathophysiology of 16p11.2 copy number variation and establish TAOK2 kinase as a regulator of primary cilium length.