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:10.1101/2021.10.25.465808

Cited by 2 publications

(1 citation statement)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Individual overexpression of cDNAs cannot reproduce the effects of simultaneous overexpression of chromosome 21 genes in the context of trisomy or detect genetic interactions between sets of trisomic genes. Our library contains most conserved chromosome 21 protein-coding genes but does not include several genes that may influence neurodevelopment, including PCNT and SON ( 23, 74-76 ). Transient transfection likely causes supraphysiological overexpression of cDNAs, and we did not comprehensively confirm expression of each cDNA, leading to possible false negatives.…”

Section: Discussionmentioning

confidence: 99%

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

Moyer

Fernandez

et al. 2022

Preprint

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Moyer

Fernandez

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

Trisomy 21 induces pericentrosomal crowding disrupting early stages of primary ciliogenesis and mouse cerebellar development

Jewett

McCurdy

O’Toole

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

SummaryPrimary cilia are signaling organelles essential for development and homeostasis. Loss of primary cilia is lethal, and decreased or defective cilia cause multisystemic conditions called ciliopathies. Down syndrome shares clinical overlap with ciliopathies. We previously showed that trisomy 21 diminishes primary cilia formation and function due to elevated Pericentrin, a centrosome protein encoded on chromosome 21. Pericentrin is mislocalized, creating aggregates that disrupt pericentrosomal trafficking and microtubule organization. Here, we examine the cilia-related molecules and pathways disrupted in trisomy 21 and their in vivo phenotypic relevance. Utilizing ciliogenesis time course experiments, we reveal how Pericentrin, microtubule networks, and components of ciliary vesicles are reorganized for ciliogenesis in euploid cells. Early in ciliogenesis, chromosome 21 polyploidy results in elevated Pericentrin and microtubule networks away from the centrosome that ensnare MyosinVA and EHD1, blocking mother centriole uncapping that is essential for ciliogenesis. Ciliated trisomy 21 cells have persistent trafficking defects that reduce transition zone protein localization, which is critical for Sonic hedgehog signaling. Sonic hedgehog signaling is decreased and anticorrelates with Pericentrin levels in trisomy 21 primary mouse embryonic fibroblasts. Finally, we observe decreased ciliation in vivo. A mouse model of Down syndrome with elevated Pericentrin has fewer primary cilia in cerebellar granule neuron progenitors and thinner external granular layers. Our work reveals that elevated Pericentrin in trisomy 21 disrupts multiple early steps of ciliogenesis and creates persistent trafficking defects in ciliated cells. This pericentrosomal crowding results in signaling defects consistent with the neurological deficits found in individuals with Down syndrome.

show abstract

Trisomy 21 increases microtubules and disrupts centriolar satellite localization

Cited by 2 publications

References 49 publications

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

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

Trisomy 21 induces pericentrosomal crowding disrupting early stages of primary ciliogenesis and mouse cerebellar development

Contact Info

Product

Resources

About