Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 33, Issue 8, Pages -Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E21-10-0517-T
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Funding
- Linda Crnic Institute for Down Syndrome
- Global Down Syndrome Foundation
- [NIH-NIGMS R01 GM-138415]
- [NIH-NIGMS R35 GM-140813]
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Trisomy 21 leads to increased PCNT protein, which disrupts primary cilia formation and signaling. Enlarged cytoplasmic puncta of PCNT affect the density and stability of the microtubule network, leading to defects in cilia. Decreasing PCNT can alleviate these defects in trisomy 21 cells.
Trisomy 21, the source of Down syndrome, causes a 0.5-fold protein increase of the chromosome 21-resident gene Pericentrin (PCNT) and reduces primary cilia formation and signaling. We investigate how PCNT imbalances disrupt cilia. Using isogenic RPE-1 cells with increased chromosome 21 dosage, we find PCNT accumulates around the centrosome as a cluster of enlarged cytoplasmic puncta that localize along microtubules (MTs) and at MT ends. Cytoplasmic PCNT puncta impact the density, stability, and localization of the MT trafficking network required for primary cilia. The PCNT puncta appear to sequester cargo peripheral to centrosomes in what we call pericentrosomal crowding. The centriolar satellite proteins PCM1, CEP131, and CEP290, important for ciliogenesis, accumulate at enlarged PCNT puncta in trisomy 21 cells. Reducing PCNT when chromosome 21 ploidy is elevated is sufficient to decrease PCNT puncta and pericentrosomal crowding, reestablish a normal density of MTs around the centrosome, and restore ciliogenesis to wild-type levels. A transient reduction in MTs also decreases pericentrosomal crowding and partially rescues ciliogenesis in trisomy 21 cells, indicating that increased PCNT leads to defects in the MT network deleterious to normal centriolar satellite distribution. We propose that chromosome 21 aneuploidy disrupts MT-dependent intracellular trafficking required for primary cilia.
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