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Trisomy 21 increases microtubules and disrupts centriolar satellite localization
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 fi...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9635274/ https://www.ncbi.nlm.nih.gov/pubmed/35476505 http://dx.doi.org/10.1091/mbc.E21-10-0517-T |
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author | McCurdy, Bailey L. Jewett, Cayla E. Stemm-Wolf, Alexander J. Duc, Huy Nguyen Joshi, Molishree Espinosa, Joaquin M. Prekeris, Rytis Pearson, Chad G. |
author_facet | McCurdy, Bailey L. Jewett, Cayla E. Stemm-Wolf, Alexander J. Duc, Huy Nguyen Joshi, Molishree Espinosa, Joaquin M. Prekeris, Rytis Pearson, Chad G. |
author_sort | McCurdy, Bailey L. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9635274 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-96352742022-11-07 Trisomy 21 increases microtubules and disrupts centriolar satellite localization McCurdy, Bailey L. Jewett, Cayla E. Stemm-Wolf, Alexander J. Duc, Huy Nguyen Joshi, Molishree Espinosa, Joaquin M. Prekeris, Rytis Pearson, Chad G. Mol Biol Cell Brief Reports 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. The American Society for Cell Biology 2022-06-13 /pmc/articles/PMC9635274/ /pubmed/35476505 http://dx.doi.org/10.1091/mbc.E21-10-0517-T Text en © 2022 McCurdy et al. “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial-Share Alike 4.0 International Creative Commons License. |
spellingShingle | Brief Reports McCurdy, Bailey L. Jewett, Cayla E. Stemm-Wolf, Alexander J. Duc, Huy Nguyen Joshi, Molishree Espinosa, Joaquin M. Prekeris, Rytis Pearson, Chad G. Trisomy 21 increases microtubules and disrupts centriolar satellite localization |
title | Trisomy 21 increases microtubules and disrupts centriolar satellite localization |
title_full | Trisomy 21 increases microtubules and disrupts centriolar satellite localization |
title_fullStr | Trisomy 21 increases microtubules and disrupts centriolar satellite localization |
title_full_unstemmed | Trisomy 21 increases microtubules and disrupts centriolar satellite localization |
title_short | Trisomy 21 increases microtubules and disrupts centriolar satellite localization |
title_sort | trisomy 21 increases microtubules and disrupts centriolar satellite localization |
topic | Brief Reports |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9635274/ https://www.ncbi.nlm.nih.gov/pubmed/35476505 http://dx.doi.org/10.1091/mbc.E21-10-0517-T |
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