Embryonic organizer formation disorder leads to multiorgan dysplasia in Down syndrome.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
19 12 2022
19 12 2022
Historique:
received:
17
08
2022
accepted:
12
12
2022
revised:
08
12
2022
entrez:
19
12
2022
pubmed:
20
12
2022
medline:
22
12
2022
Statut:
epublish
Résumé
Despite the high prevalence of Down syndrome (DS) and early identification of the cause (trisomy 21), its molecular pathogenesis has been poorly understood and specific treatments have consequently been practically unavailable. A number of medical conditions throughout the body associated with DS have prompted us to investigate its molecular etiology from the viewpoint of the embryonic organizer, which can steer the development of surrounding cells into specific organs and tissues. We established a DS zebrafish model by overexpressing the human DYRK1A gene, a highly haploinsufficient gene located at the "critical region" within 21q22. We found that both embryonic organizer and body axis were significantly impaired during early embryogenesis, producing abnormalities of the nervous, heart, visceral, and blood systems, similar to those observed with DS. Quantitative phosphoproteome analysis and related assays demonstrated that the DYRK1A-overexpressed zebrafish embryos had anomalous phosphorylation of β-catenin and Hsp90ab1, resulting in Wnt signaling enhancement and TGF-β inhibition. We found an uncovered ectopic molecular mechanism present in amniocytes from fetuses diagnosed with DS and isolated hematopoietic stem cells (HSCs) of DS patients. Importantly, the abnormal proliferation of DS HSCs could be recovered by switching the balance between Wnt and TGF-β signaling in vitro. Our findings provide a novel molecular pathogenic mechanism in which ectopic Wnt and TGF-β lead to DS physical dysplasia, suggesting potential targeted therapies for DS.
Identifiants
pubmed: 36535930
doi: 10.1038/s41419-022-05517-x
pii: 10.1038/s41419-022-05517-x
pmc: PMC9763398
doi:
Substances chimiques
Transforming Growth Factor beta
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1054Informations de copyright
© 2022. The Author(s).
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