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The role of Lrp6-mediated Wnt/ß-catenin signaling in the development and intervention of spinal neural tube defects in mice.
Zhao, Tianyu; McMahon, Moira; Reynolds, Kurt; Saha, Subbroto Kumar; Stokes, Arjun; Zhou, Chengji J.
Afiliação
  • Zhao T; Institute for Pediatric Regenerative Medicine of Shriners Hospitals for Children-Northern California, Department of Biochemistry and Molecular Medicine, University of California, Davis School of Medicine, Sacramento, CA 95817, USA.
  • McMahon M; Institute for Pediatric Regenerative Medicine of Shriners Hospitals for Children-Northern California, Department of Biochemistry and Molecular Medicine, University of California, Davis School of Medicine, Sacramento, CA 95817, USA.
  • Reynolds K; Institute for Pediatric Regenerative Medicine of Shriners Hospitals for Children-Northern California, Department of Biochemistry and Molecular Medicine, University of California, Davis School of Medicine, Sacramento, CA 95817, USA.
  • Saha SK; Institute for Pediatric Regenerative Medicine of Shriners Hospitals for Children-Northern California, Department of Biochemistry and Molecular Medicine, University of California, Davis School of Medicine, Sacramento, CA 95817, USA.
  • Stokes A; Institute for Pediatric Regenerative Medicine of Shriners Hospitals for Children-Northern California, Department of Biochemistry and Molecular Medicine, University of California, Davis School of Medicine, Sacramento, CA 95817, USA.
  • Zhou CJ; Institute for Pediatric Regenerative Medicine of Shriners Hospitals for Children-Northern California, Department of Biochemistry and Molecular Medicine, University of California, Davis School of Medicine, Sacramento, CA 95817, USA.
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

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