Heart induction by Wnt antagonists depends on the homeodomain transcription factor Hex
Open accessAbstract
Inhibition of canonical Wnt/β-catenin signaling by Dickkopf-1 (Dkk-1) or Crescent initiates cardiogenesis in vertebrate embryos. However, nearly nothing is known about the downstream effectors of these secreted Wnt antagonists or the mechanism by which they activate heart formation. Here we show that Wnt antagonists in Xenopus stimulate cardiogenesis non-cell-autonomously, up to several cells away from those in which canonical Wnt/β-catenin signaling is blocked, indicative of an indirect role in heart induction. A screen for downstream mediators revealed that Dkk-1 and other inhibitors of the canonical Wnt pathway induce the homeodomain transcription factor Hex, which is normally expressed in endoderm underlying the presumptive cardiac mesoderm in amphibian, bird, and mammalian embryos. Loss of Hex function blocks both endogenous heart development and ectopic heart induction by Dkk-1. As with the canonical Wnt pathway antagonists, ectopic Hex induces expression of cardiac markers non-cell-autonomously. Thus, to initiate cardiogenesis, Wnt antagonists act on endoderm to up-regulate Hex, which, in turn, controls production of a diffusible heart-inducing factor. This novel function for Hex suggests an etiology for the cardiac malformations in Hex mutant mice and will make possible the isolation of factors that induce heart directly in the mesoderm.
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- Authors
- Foley, A. C., & Mercola, M.
- Affiliations
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2005-02-01
- Volume
- 19
- Issue
- 3
- Pages
- 387-396
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC546516
- OpenAlex
- W2133447907
- Cited by
- 195
- References
- 71
- Citations by year
- 2025: 3 · 2024: 2 · 2023: 2 · 2022: 1 · 2021: 8 · 2020: 4 · 2019: 4 · 2018: 4 · 2017: 5 · 2016: 10 · 2015: 8 · 2014: 12 · 2013: 9 · 2012: 8
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (HL59502)
- National Heart, Lung, and Blood Institute (R01HL059502, R01 HL67079, F32 HL 69595, R01HL067079, F32HL069595, R01 HL59502)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- heart development, Wnt antagonists, DKK1, crescents, canonical Wnt/β-catenin pathway, endoderm, non-cell-autonomous signaling, cardiac anomalies, Xenopus embryo
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Animals, Embryonic Induction, Epistasis, Genetic, Heart, Proteins, RNA, Messenger, Transcription Factors, Xenopus, Biomarkers, Homeodomain Proteins, Gene Expression Regulation, Developmental, HMGB Proteins, Xenopus Proteins, Intercellular Signaling Peptides and Proteins, Glycogen Synthase Kinase 3, Epigenesis, Genetic, Wnt Proteins, Mice, TCF Transcription Factors, Transcription Factor 7-Like 1 Protein
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