Document Type
Article
Publication Date
1-19-2023
Original Citation
Jewett C,
McCurdy B,
O'Toole E,
Stemm-Wolf A,
Given K,
Lin C,
Olsen V,
Martin W,
Reinholdt L,
Espinosa J,
Sullivan K,
Macklin W,
Prekeris R,
Pearson C.
Trisomy 21 induces pericentrosomal crowding delaying primary ciliogenesis and mouse cerebellar development. Elife. 2023;12.
Keywords
JMG, Mice, Animals, Down Syndrome, Hedgehog Proteins, Centrioles, Centrosome, Cilia
JAX Source
Elife. 2023;12.
ISSN
2050-084X
PMID
36656118
DOI
https://doi.org/10.7554/eLife.78202
Grant
This research was funded by NIH R01GM138415 and R35GM140813 to CGP, NSF Graduate Research Fellowship DGE-1553798, NIH INCLUDE T32 supple- ment GM008730, and Blumenthal Fellowship to CEJ, and NIH R01DK064380 to RP. CEJ, JME, KDS, and CGP are members of the Linda Crnic Institute for Down syndrome.
Abstract
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.
Comments
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