The role of Lrp6-mediated Wnt/ß-catenin signaling in the development and intervention of spinal neural tube defects in mice.
Dis Model Mech
; 15(6)2022 06 01.
Article
em En
| MEDLINE
| ID: mdl-35514236
Neural tube defects (NTDs) are among the common and severe birth defects with poorly understood etiology. Mutations in the Wnt co-receptor LRP6 are associated with NTDs in humans. Either gain-of-function (GOF) or loss-of-function (LOF) mutations of Lrp6 can cause NTDs in mice. NTDs in Lrp6-GOF mutants may be attributed to altered ß-catenin-independent noncanonical Wnt signaling. However, the mechanisms underlying NTDs in Lrp6-LOF mutants and the role of Lrp6-mediated canonical Wnt/ß-catenin signaling in neural tube closure remain unresolved. We previously demonstrated that ß-catenin signaling is required for posterior neuropore (PNP) closure. In the current study, conditional ablation of Lrp6 in dorsal PNP caused spinal NTDs with diminished activities of Wnt/ß-catenin signaling and its downstream target gene Pax3, which is required for PNP closure. ß-catenin-GOF rescued NTDs in Lrp6-LOF mutants. Moreover, maternal supplementation of a Wnt/ß-catenin signaling agonist reduced the frequency and severity of spinal NTDs in Lrp6-LOF mutants by restoring Pax3 expression. Together, these results demonstrate the essential role of Lrp6-mediated Wnt/ß-catenin signaling in PNP closure, which could also provide a therapeutic target for NTD intervention through manipulation of canonical Wnt/ß-catenin signaling activities.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Via de Sinalização Wnt
/
Defeitos do Tubo Neural
Limite:
Animals
Idioma:
En
Revista:
Dis Model Mech
Ano de publicação:
2022
Tipo de documento:
Article