β-catenin regulates Pax3 and Cdx2 for caudal neural tube closure and elongation.

Abstract

Non-canonical Wnt/planar cell polarity (PCP) signaling plays a primary role in the convergent extension that drives neural tube closure and body axis elongation. PCP signaling gene mutations cause severe neural tube defects (NTDs). However, the role of canonical Wnt/β-catenin signaling in neural tube closure and NTDs remains poorly understood. This study shows that conditional gene targeting of β-catenin in the dorsal neural folds of mouse embryos represses the expression of the homeobox-containing genes Pax3 and Cdx2 at the dorsal posterior neuropore (PNP), and subsequently diminishes the expression of the Wnt/β-catenin signaling target genes T, Tbx6 and Fgf8 at the tail bud, leading to spina bifida aperta, caudal axis bending and tail truncation. We demonstrate that Pax3 and Cdx2 are novel downstream targets of Wnt/β-catenin signaling. Transgenic activation of Pax3 cDNA can rescue the closure defect in the β-catenin mutants, suggesting that Pax3 is a key downstream effector of β-catenin signaling in the PNP closure process. Cdx2 is known to be crucial in posterior axis elongation and in neural tube closure. We found that Cdx2 expression is also repressed in the dorsal PNPs of Pax3-null embryos. However, the ectopically activated Pax3 in the β-catenin mutants cannot restore Cdx2 mRNA in the dorsal PNP, suggesting that the presence of both β-catenin and Pax3 is required for regional Cdx2 expression. Thus, β-catenin signaling is required for caudal neural tube closure and elongation, acting through the transcriptional regulation of key target genes in the PNP.

• Authors: Tianyu Zhao, Qini Gan, Arjun Stokes, Rhonda N T Lassiter, Yongping Wang, Jason Chan, Jane X Han, David E Pleasure, Jonathan A Epstein, Chengji J Zhou
• Journal: Development (Cambridge, England) (Development) Vol. 141 Issue 1 Pg. 148-57 (Jan 2014) ISSN: 1477-9129 [Electronic] England
• PMID: 24284205 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CDX2 Transcription Factor
• Cdx2 protein, mouse
• Fgf8 protein, mouse
• Homeodomain Proteins
• MSX1 Transcription Factor
• Msx1 protein, mouse
• PAX3 Transcription Factor
• Paired Box Transcription Factors
• T-Box Domain Proteins
• Tbx6 protein, mouse
• Transcription Factors
• Wnt Proteins
• beta Catenin
• Pax3 protein, mouse
• Fibroblast Growth Factor 8

Topics

• Animals
• Body Patterning (genetics, physiology)
• CDX2 Transcription Factor
• Cell Adhesion (genetics)
• Cell Polarity (physiology)
• Fibroblast Growth Factor 8 (biosynthesis)
• Gene Expression Regulation, Developmental
• Homeodomain Proteins (biosynthesis, genetics, metabolism)
• MSX1 Transcription Factor (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neural Tube (embryology, growth & development, metabolism)
• Neural Tube Defects (genetics)
• Neurulation
• PAX3 Transcription Factor
• Paired Box Transcription Factors (biosynthesis, genetics, metabolism)
• Spinal Dysraphism (genetics)
• T-Box Domain Proteins
• Transcription Factors (biosynthesis, genetics, metabolism)
• Transcription, Genetic
• Wnt Proteins (genetics, metabolism)
• Wnt Signaling Pathway (genetics)
• beta Catenin (genetics, metabolism)