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Retinoic acid induces down-regulation of Wnt-3a, apoptosis and diversion of tail bud cells to a neural fate in the mouse embryo.
- Source :
-
Mechanisms of development [Mech Dev] 1999 Jun; Vol. 84 (1-2), pp. 17-30. - Publication Year :
- 1999
-
Abstract
- The tail bud comprises the caudal extremity of the vertebrate embryo, containing a pool of pluripotent mesenchymal stem cells that gives rise to almost all the tissues of the sacro-caudal region. Treatment of pregnant mice with 100 mg/kg all-trans retinoic acid at 9.5 days post coitum induces severe truncation of the body axis, providing a model system for studying the mechanisms underlying development of caudal agenesis. In the present study, we find that retinoic acid treatment causes extensive apoptosis of tail bud cells 24 h after treatment. Once the apoptotic cells have been removed, the remaining mesenchymal cells differentiate into an extensive network of ectopic tubules, radially arranged around the notochord. These tubules express Pax-3 and Pax-6 in a regionally-restricted pattern that closely resembles expression in the definitive neural tube. Neurofilament-positive neurons subsequently grow out from the ectopic tubules. Thus, the tail bud cells remaining after retinoic acid-induced apoptosis appear to adopt a neural fate. Wnt-3a, a gene that has been shown to be essential for tail bud formation, is specifically down-regulated in the tail bud of retinoic acid-treated embryos, as early as 2 h after retinoic acid treatment and Wnt-3a transcripts become undetectable by 10 h. In contrast, Wnt-5a and RAR-gamma are still detectable in the tail bud at that time. Extensive cell death also occurs in the tail bud of embryos homozygous for the vestigial tail mutation, in which there is a marked reduction in Wnt-3a expression. These embryos go on to develop multiple neural tubes in their truncated caudal region. These results suggest that retinoic acid induces down-regulation of Wnt-3a which may play an important role in the pathogenesis of axial truncation, involving induction of widespread apoptosis, followed by an alteration of tail bud cell fate to form multiple ectopic neural tubes.
- Subjects :
- Animals
Apoptosis drug effects
Cell Death drug effects
Cell Differentiation
DNA-Binding Proteins genetics
DNA-Binding Proteins metabolism
Dose-Response Relationship, Drug
Down-Regulation
Embryo, Mammalian drug effects
Eye Proteins
Female
Homozygote
Male
Mesoderm drug effects
Mesoderm metabolism
Mice
Mice, Inbred ICR
Mutation
Nervous System drug effects
Nervous System metabolism
Nervous System Malformations chemically induced
Nervous System Malformations embryology
Neurons
PAX3 Transcription Factor
PAX6 Transcription Factor
Paired Box Transcription Factors
Pregnancy
Proteins drug effects
Repressor Proteins
Tail cytology
Tail drug effects
Tretinoin metabolism
Wnt Proteins
Wnt3 Protein
Wnt3A Protein
Homeodomain Proteins
Nervous System embryology
Proteins metabolism
Tail embryology
Transcription Factors
Tretinoin pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0925-4773
- Volume :
- 84
- Issue :
- 1-2
- Database :
- MEDLINE
- Journal :
- Mechanisms of development
- Publication Type :
- Academic Journal
- Accession number :
- 10473117
- Full Text :
- https://doi.org/10.1016/s0925-4773(99)00059-3