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Exploiting spatiotemporal regulation of FZD5 during neural patterning for efficient ventral midbrain specification.
Yang, Andy; Chidiac, Rony; Russo, Emma; Steenland, Hendrik; Pauli, Quinn; Bonin, Robert; Blazer, Levi L; Adams, Jarrett J; Sidhu, Sachdev S; Goeva, Aleksandrina; Salahpour, Ali; Angers, Stephane.
Afiliación
  • Yang A; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada.
  • Chidiac R; Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada.
  • Russo E; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada.
  • Steenland H; Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada.
  • Pauli Q; Department of Pharmacology and Toxicology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Bonin R; Department of Pharmacology and Toxicology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Blazer LL; NeuroTek Innovative Technology, Toronto, ON M6C 3A2, Canada.
  • Adams JJ; Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada.
  • Sidhu SS; Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada.
  • Goeva A; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada.
  • Salahpour A; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada.
  • Angers S; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada.
Development ; 151(5)2024 Mar 01.
Article en En | MEDLINE | ID: mdl-38358799
ABSTRACT
The Wnt/ß-catenin signaling governs anterior-posterior neural patterning during development. Current human pluripotent stem cell (hPSC) differentiation protocols use a GSK3 inhibitor to activate Wnt signaling to promote posterior neural fate specification. However, GSK3 is a pleiotropic kinase involved in multiple signaling pathways and, as GSK3 inhibition occurs downstream in the signaling cascade, it bypasses potential opportunities for achieving specificity or regulation at the receptor level. Additionally, the specific roles of individual FZD receptors in anterior-posterior patterning are poorly understood. Here, we have characterized the cell surface expression of FZD receptors in neural progenitor cells with different regional identity. Our data reveal unique upregulation of FZD5 expression in anterior neural progenitors, and this expression is downregulated as cells adopt a posterior fate. This spatial regulation of FZD expression constitutes a previously unreported regulatory mechanism that adjusts the levels of ß-catenin signaling along the anterior-posterior axis and possibly contributes to midbrain-hindbrain boundary formation. Stimulation of Wnt/ß-catenin signaling in hPSCs, using a tetravalent antibody that selectively triggers FZD5 and LRP6 clustering, leads to midbrain progenitor differentiation and gives rise to functional dopaminergic neurons in vitro and in vivo.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Glucógeno Sintasa Quinasa 3 / Beta Catenina / Receptores Frizzled Límite: Animals / Humans Idioma: En Revista: Development Asunto de la revista: BIOLOGIA / EMBRIOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Glucógeno Sintasa Quinasa 3 / Beta Catenina / Receptores Frizzled Límite: Animals / Humans Idioma: En Revista: Development Asunto de la revista: BIOLOGIA / EMBRIOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Reino Unido