Department of Cell and Developmental Biology, University of Colorado-Anschutz Medical Campus, Aurora, CO 80045, USA; Linda Crnic Institute for Down Syndrome, University of Colorado-Anschutz Medical Campus, Aurora, CO 80045, USA.
Department of Pharmacology, University of Colorado-Anschutz Medical Campus, Aurora, CO 80045, USA; Linda Crnic Institute for Down Syndrome, University of Colorado-Anschutz Medical Campus, Aurora, CO 80045, USA.
Dev Cell. 2018 Sep 10;46(5):641-650.e6. doi: 10.1016/j.devcel.2018.07.008. Epub 2018 Aug 9.
Trisomy 21 (T21) is the most prevalent human chromosomal disorder, causing a range of cardiovascular, musculoskeletal, and neurological abnormalities. However, the cellular processes disrupted by T21 are poorly understood. Consistent with the clinical overlap between T21 and ciliopathies, we discovered that T21 disrupts cilia formation and signaling. Cilia defects arise from increased expression of Pericentrin, a centrosome scaffold and trafficking protein encoded on chromosome 21. Elevated Pericentrin is necessary and sufficient for T21 cilia defects. Pericentrin accumulates at centrosomes and dramatically in the cytoplasm surrounding centrosomes. Centrosome Pericentrin recruits more γ-tubulin and enhances microtubules, whereas cytoplasmic Pericentrin assembles into large foci that do not efficiently traffic. Moreover, the Pericentrin-associated cilia assembly factor IFT20 and the ciliary signaling molecule Smoothened do not efficiently traffic to centrosomes and cilia. Thus, increased centrosome protein dosage produces ciliopathy-like outcomes in T21 cells by decreasing trafficking between the cytoplasm, centrosomes, and cilia.
三体 21（T21）是最常见的人类染色体疾病，导致一系列心血管、肌肉骨骼和神经异常。然而，T21 破坏的细胞过程知之甚少。与 T21 和纤毛病之间的临床重叠一致，我们发现 T21 会破坏纤毛的形成和信号传递。纤毛缺陷是由于 21 号染色体上编码的中心体支架和运输蛋白 Pericentrin 表达增加引起的。升高的 Pericentrin 对于 T21 的纤毛缺陷是必要且充分的。Pericentrin 在中心体周围的细胞质中大量积累。中心体 Pericentrin 募集更多的γ微管蛋白并增强微管，而细胞质 Pericentrin 组装成不能有效运输的大焦点。此外，Pericentrin 相关的纤毛组装因子 IFT20 和纤毛信号分子 Smoothened 不能有效地运输到中心体和纤毛。因此，增加中心体蛋白剂量会通过减少细胞质、中心体和纤毛之间的运输，在 T21 细胞中产生纤毛病样的结果。
