Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: McCurdy, Bailey L., Jewett, Cayla E., Stemm-Wolf, Alexander J., Duc, Huy Nguyen, Joshi, Molishree, Espinosa, Joaquin M., Prekeris, Rytis, Pearson, Chad G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2022
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
_version_ 1784824677829443584
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
work_keys_str_mv AT mccurdybaileyl trisomy21increasesmicrotubulesanddisruptscentriolarsatellitelocalization
AT jewettcaylae trisomy21increasesmicrotubulesanddisruptscentriolarsatellitelocalization
AT stemmwolfalexanderj trisomy21increasesmicrotubulesanddisruptscentriolarsatellitelocalization
AT duchuynguyen trisomy21increasesmicrotubulesanddisruptscentriolarsatellitelocalization
AT joshimolishree trisomy21increasesmicrotubulesanddisruptscentriolarsatellitelocalization
AT espinosajoaquinm trisomy21increasesmicrotubulesanddisruptscentriolarsatellitelocalization
AT prekerisrytis trisomy21increasesmicrotubulesanddisruptscentriolarsatellitelocalization
AT pearsonchadg trisomy21increasesmicrotubulesanddisruptscentriolarsatellitelocalization