CAG repeat instability in embryonic stem cells and derivative spermatogenic cells of transgenic Huntington's disease monkey.
Adult Germline Stem Cells
/ pathology
Animals
Animals, Genetically Modified
/ genetics
Cell Differentiation
/ genetics
Disease Models, Animal
Embryonic Stem Cells
/ pathology
Genomic Instability
/ genetics
Humans
Huntington Disease
/ genetics
Macaca mulatta
/ genetics
Male
Microsatellite Instability
Trinucleotide Repeats
/ genetics
CAG repeat instability
Genetic anticipation
HD rhesus monkey embryonic stem cells (rESCs)
Huntington’s disease
Spermatogenic cells
Journal
Journal of assisted reproduction and genetics
ISSN: 1573-7330
Titre abrégé: J Assist Reprod Genet
Pays: Netherlands
ID NLM: 9206495
Informations de publication
Date de publication:
May 2021
May 2021
Historique:
received:
07
12
2020
accepted:
08
02
2021
pubmed:
22
2
2021
medline:
9
9
2021
entrez:
21
2
2021
Statut:
ppublish
Résumé
The expansion of CAG (glutamine; Q) trinucleotide repeats (TNRs) predominantly occurs through male lineage in Huntington's disease (HD). As a result, offspring will have larger CAG repeats compared to their fathers, which causes an earlier onset of the disease called genetic anticipation. This study aims to develop a novel in vitro model to replicate CAG repeat instability in early spermatogenesis and demonstrate the biological process of genetic anticipation by using the HD stem cell model for the first time. HD rhesus monkey embryonic stem cells (rESCs) were cultured in vitro for an extended period. Male rESCs were used to derive spermatogenic cells in vitro with a 10-day differentiation. The assessment of CAG repeat instability was performed by GeneScan and curve fit analysis. Spermatogenic cells derived from rESCs exhibit progressive expansion of CAG repeats with high daily expansion rates compared to the extended culture of rESCs. The expansion of CAG repeats is cell type-specific and size-dependent. Here, we report a novel stem cell model that replicates genome instability and CAG repeat expansion in in vitro derived HD monkey spermatogenic cells. The in vitro spermatogenic cell model opens a new opportunity for studying TNR instability and the underlying mechanism of genetic anticipation, not only in HD but also in other TNR diseases.
Identifiants
pubmed: 33611676
doi: 10.1007/s10815-021-02106-3
pii: 10.1007/s10815-021-02106-3
pmc: PMC8190423
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1215-1229Subventions
Organisme : NINDS NIH HHS
ID : R01 NS101701
Pays : United States
Organisme : NIH HHS
ID : OD020182
Pays : United States
Organisme : NIH HHS
ID : NS101701
Pays : United States
Organisme : NIH HHS
ID : OD010930
Pays : United States
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