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Quantitative phosphoproteomic analysis of the effect of deletion and duplication of the 16p11.2 genomic locus on induced pluripotent stem cells-derived neural progenitor cells

ABSTRACT: Deletion and duplication of the 16p11.2 genomic locus are associated with opposing changes in brain size. To determine cellular mechanisms that might underlie these opposing phenotypes, we performed quantitative phosphoproteomics on induced pluripotent stem cells (iPSC) derived neural progenitor cells (NPCs) obtained from unaffected individuals, 16p11.2 deletion, and 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. TAOK2 and PPP4C were found to regulate primary cilia length. NPCs lacking TAOK2, a protein kinase, exhibited elongated cilia, aberrant IFT88 and pericentrin accumulation, and impaired 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.

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ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Neural Progenitor Cell

SUBMITTER: Juan Oses-Prieto

LAB HEAD: Smita Yadav

PROVIDER: PXD066614 | Pride | 2025-07-28

REPOSITORIES: Pride

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Project description:Study Smoking and COPD are associated with decreased mucociliary clearance and healthy smokers have shorter cilia in the large airway than nonsmokers. Intraflagellar transport (IFT) is the process by which cilia are produced and maintained. We assessed expression of IFT-related genes in smokers and nonsmokers and evaluated cilia length in the large and small airway of nonsmokers, healthy smokers, and smokers with COPD. Methods Airway epithelium was obtained via bronchoscopic brushing. Affymetrix microarrays were used to evaluate IFT gene expression in 2 independent data sets from large and small airway. Cilia length was assessed by measuring 100 cilia (10 cilia on each of 10 cells) per subject. Results All 40 IFT genes were expressed in the human large and small airway epithelium. In the large airway, 10 IFT genes were down-regulated and 1 up-regulated in smokers. In the small airway, 11 genes were down-regulated and 3 up-regulated in smokers. A set of 8 IFT genes was down-regulated in both data sets. In the large and small airway epithelium, cilia were significantly shorter in healthy smokers than nonsmokers, and significantly shorter in COPD smokers than in both healthy smokers and nonsmokers. Answer to the Question These results support the concept that loss of cilia length contributes to defective mucociliary clearance in COPD, and that smoking-induced changes in expression of IFT genes may be one mechanism of abnormally short cilia in smokers. Strategies to normalize cilia length may be an important avenue for novel COPD therapies. Gene expression was assessed for 40 intraflagellar transport related genes in the LAE of nonsmokers (n=21) and healthy smokers (n=31) and the SAE of an independent group of nonsmokers (n=28) and healthy smokers (n=69). Cilia length was assessed in a total of 228 airway epithelium samples, including 120 LAE samples and 108 SAE samples; a subset of the 228 samples is represented among the 149 samples in this Series.

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Quantitative phosphoproteomic analysis of the effect of deletion and duplication of the 16p11.2 genomic locus on induced pluripotent stem cells-derived neural progenitor cells

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