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, Joaquín M.; Prekeris, Rytis; Pearson, Chad G.

doi:10.1091/mbc.e21-10-0517-t

Cited by 7 publications

(18 citation statements)

References 54 publications

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Section: Resultsmentioning

confidence: 99%

“…PCNT is encoded on HSA21 resulting in 1.5-fold increased expression in trisomy 21 ( Galati et al, 2018 ; McCurdy et al, 2022 ). We previously showed that elevated PCNT protein is sufficient for decreased ciliation in trisomy 21 cells ( Galati et al, 2018 ; McCurdy et al, 2022 ). Whereas PCNT normally organizes microtubules emanating from centrosomes, elevated PCNT has three major consequences in trisomy 21 cells ( Figure 1A ): (1) PCNT increases microtubule density around the centrosome; (2) PCNT forms large protein aggregates along these microtubules; and (3) PCNT resides at the ends of cytoplasmic microtubules that are disconnected from the centrosome ( Galati et al, 2018 ; McCurdy et al, 2022 ).…”

Section: Resultsmentioning

confidence: 99%

“…We previously showed that elevated PCNT protein is sufficient for decreased ciliation in trisomy 21 cells ( Galati et al, 2018 ; McCurdy et al, 2022 ). Whereas PCNT normally organizes microtubules emanating from centrosomes, elevated PCNT has three major consequences in trisomy 21 cells ( Figure 1A ): (1) PCNT increases microtubule density around the centrosome; (2) PCNT forms large protein aggregates along these microtubules; and (3) PCNT resides at the ends of cytoplasmic microtubules that are disconnected from the centrosome ( Galati et al, 2018 ; McCurdy et al, 2022 ). Consistent with more microtubules, the centrosome scaffolding proteins CDK5RAP2 and γ-tubulin are increased at and around the centrosome in trisomy 21 cells, although unlike PCNT, the whole cell expression levels of these proteins are unchanged ( Galati et al, 2018 ).…”

Section: Resultsmentioning

confidence: 99%

“…Together, elevated PCNT perturbs trafficking to and from centrosomes by altering microtubule networks and the molecular composition of the pericentrosomal region, thereby hindering the exchange of molecules required for ciliogenesis – a phenotype we have termed pericentrosomal crowding. This model was derived from an analysis of either cycling cells or cells 24 hr after serum depletion (0.5% serum in medium) to induce G0 cell cycle arrest and ciliogenesis ( Galati et al, 2018 ; McCurdy et al, 2022 ). Because ciliogenesis requires a coordinated series of trafficking and centrosome remodeling events over a period of several hours, we explored how elevated PCNT and trisomy 21 disrupts these processes.…”

Section: Resultsmentioning

confidence: 99%

“…PCNT is encoded on human chromosome 21 (human somatic autosome 21; HSA21), and we previously showed that elevated PCNT due to increased copy number in trisomy 21 is sufficient to initiate cilia defects in human DS-derived fibroblasts compared to age- and sex-matched controls ( Galati et al, 2018 ). Elevated PCNT forms aggregates that colocalize with centriolar satellite proteins such as PCM1 and disrupts the flux of intracellular components to and from the centrosome ( McCurdy et al, 2022 ). While we showed reduced centrosome localization of the ciliary IFT20 protein in trisomy 21 cells ( Galati et al, 2018 ), IFT20 recruitment to the cilium is a late step in the process of ciliogenesis ( Lu et al, 2015 ; Joo et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

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Trisomy 21 induces pericentrosomal crowding delaying primary ciliogenesis and mouse cerebellar development

Jewett

McCurdy

O’Toole

et al. 2023

eLife

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Trisomy 21, the genetic cause of Down syndrome, disrupts primary cilia formation and function, in part through elevated Pericentrin, a centrosome protein encoded on chromosome 21. Yet how trisomy 21 and elevated Pericentrin disrupt cilia-related molecules and pathways, and the in vivo phenotypic relevance remain unclear. Utilizing ciliogenesis time course experiments combined with light microscopy and electron tomography, we reveal that chromosome 21 polyploidy elevates Pericentrin and microtubules away from the centrosome that corral MyosinVA and EHD1, delaying ciliary membrane delivery and mother centriole uncapping essential for ciliogenesis. If given enough time, trisomy 21 cells eventually ciliate, but these ciliated cells demonstrate persistent trafficking defects that reduce transition zone protein localization and decrease sonic hedgehog signaling in direct anticorrelation with Pericentrin levels. Consistent with cultured trisomy 21 cells, a mouse model of Down syndrome with elevated Pericentrin has fewer primary cilia in cerebellar granule neuron progenitors and thinner external granular layers at P4. Our work reveals that elevated Pericentrin from trisomy 21 disrupts multiple early steps of ciliogenesis and creates persistent trafficking defects in ciliated cells. This pericentrosomal crowding mechanism results in signaling deficiencies consistent with the neurological phenotypes found in individuals with Down syndrome.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Trisomy 21 induces pericentrosomal crowding delaying primary ciliogenesis and mouse cerebellar development

Jewett

McCurdy

O’Toole

et al. 2023

eLife

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Host-derived protein profiles of human neonatal meconium across gestational ages

Shitara,

Konno,

Yoshihara

et al. 2024

Nat Commun

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Meconium, a non-invasive biomaterial reflecting prenatal substance accumulation, could provide valuable insights into neonatal health. However, the comprehensive protein profile of meconium across gestational ages remains unclear. Here, we conducted an extensive proteomic analysis of first meconium from 259 newborns across varied gestational ages to delineate protein composition and elucidate its relevance to neonatal diseases. The first meconium samples were collected, with the majority obtained before feeding, and the mean time for the first meconium passage from the anus was 11.9 ± 9.47 h. Our analysis revealed 5370 host-derived meconium proteins, which varied depending on sex and gestational age. Specifically, meconium from preterm infants exhibited elevated concentrations of proteins associated with the extracellular matrix. Additionally, the protein profiles of meconium also exhibited unique variations depending on both specific diseases, including gastrointestinal diseases, congenital heart diseases, and maternal conditions. Furthermore, we developed a machine learning model to predict gestational ages using meconium proteins. Our model suggests that newborns with gastrointestinal diseases and congenital heart diseases may have immature gastrointestinal systems. These findings highlight the intricate relationship between clinical parameters and meconium protein composition, offering potential for a novel approach to assess neonatal gastrointestinal health.

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Overexpression screen of chromosome 21 genes reveals modulators of Sonic hedgehog signaling relevant to Down syndrome

Moyer

Fernandez

et al. 2022

Preprint

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Dysregulation of Sonic hedgehog (SHH) signaling may contribute to multiple Down syndrome-associated phenotypes, including cerebellar hypoplasia, congenital heart defects, craniofacial and skeletal dysmorphologies, and Hirschsprung disease. Granule cell precursors isolated from the developing cerebellum of Ts65Dn mice are less responsive to the mitogenic effects of SHH than euploid cells, and a single postnatal dose of the SHH pathway agonist SAG rescues cerebellar morphology and performance on learning and memory tasks in Ts65Dn mice. SAG treatment also normalizes expression levels of OLIG2 in neural progenitor cells derived from human trisomy 21 iPSCs. However, despite evidence that activating SHH signaling can ameliorate some Down syndrome-associated phenotypes, chromosome 21 does not encode any components of the canonical SHH pathway. Here, we screened 163 chromosome 21 cDNAs in a series of SHH-responsive cell lines to identify chromosome 21 genes that modulate SHH signaling. We confirmed overexpression of trisomic candidate genes using RNA-seq in Ts65Dn and TcMAC21 cerebellum. Our study indicates that some chromosome 21 genes, including DYRK1A, upregulate SHH signaling while others, such as HMGN1 and MIS18A, inhibit SHH signaling. Overexpression of genes involved in chromatin structure and mitosis, but not genes previously implicated in ciliogenesis, regulate the SHH pathway. Our data suggest that cerebellar hypoplasia and other phenotypes related to aberrant SHH signaling arise from the net effect of trisomy for multiple chromosome 21 genes rather than the overexpression of a single trisomic gene. Identifying which chromosome 21 genes modulate SHH signaling may suggest new therapeutic avenues for ameliorating Down syndrome phenotypes.

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Trisomy 21 increases microtubules and disrupts centriolar satellite localization

Cited by 7 publications

References 54 publications

Trisomy 21 induces pericentrosomal crowding delaying primary ciliogenesis and mouse cerebellar development

Trisomy 21 induces pericentrosomal crowding delaying primary ciliogenesis and mouse cerebellar development

Host-derived protein profiles of human neonatal meconium across gestational ages

Overexpression screen of chromosome 21 genes reveals modulators of Sonic hedgehog signaling relevant to Down syndrome

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