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Retinoid-binding proteins in craniofacial development
L Dencker1, A L Gustafson, E Annerwall
1Department of Toxicology, Uppsala University, Academic Hospital, Sweden.
Abstract:
Cephalic neural crest cells are known to form the frontonasal mesenchyme and contribute to the mesenchyme of the visceral arches. Retinoids affect neural crest cells and their derivatives during development, and thus cause craniofacial, thymus, and conotruncal heart malformations. In addition, retinoids induce malformations of the central nervous system (CNS). Retinoic acid (RA) and its congeners accumulate in a saturable manner in neural crest and neural crest-derived cells, in the hindbrain, and the spinal cord of mouse embryos. Cellular retinoic acid-binding protein (CRABP) was localized by immunohistochemistry in the same areas as were the labelled RA congeners. Thus, CRABP and RA congeners were found in the transitional zone between surface ectoderm and neuropeithelium, from where neural crest cells are known to emanate (day 8 1/2). Later, specific labelling was found in the frontonasal mesenchyme and in the visceral arches. Also in the trunk, neural crest cells were labelled. In CNS, strong staining was seen in the rhombomeres (especially numbers 4-6) of the hindbrain and in the spinal cord. Retinol and cellular retinol-binding protein (CRBP) were more evenly distributed, with exception of surface ectoderm, epithelium of gut, and myocardium, where CRBP was specifically expressed. These findings are discussed in relation to the differential expression of nuclear RA receptors and homeobox genes in the craniofacial region and in the hindbrain. It is possible that RA is important for the normal pattern formation in these regions and acts as a morphogen as previously proposed in limb development.
Insights
Retinoic acid (RA) accumulates in developing neural crest cells and central nervous system (CNS) tissues. Cellular retinoic acid-binding protein (CRABP) localizes to these areas, suggesting RA
Area of Science:
- Developmental Biology
- Neuroscience
- Genetics
Background:
- Neural crest cells are crucial for craniofacial and CNS development.
- Retinoids, including retinoic acid (RA), are known teratogens causing developmental malformations.
- The precise role and localization of RA during early embryogenesis remain incompletely understood.
Purpose of the Study:
- To investigate the distribution and localization of retinoic acid (RA) and its binding proteins within the developing mouse embryo.
- To correlate RA localization with neural crest cell development and central nervous system (CNS) patterning.
- To explore the potential role of RA as a morphogen in craniofacial and hindbrain development.
Main Methods:
- Immunohistochemistry was used to localize cellular retinoic acid-binding protein (CRABP) and cellular retinol-binding protein (CRBP).
- Saturable accumulation of RA congeners in specific embryonic tissues was assessed.
- Localization patterns were analyzed in relation to neural crest cell migration pathways and CNS structures.
Main Results:
- RA congeners and CRABP showed specific, saturable accumulation in neural crest cells, frontonasal mesenchyme, visceral arches, hindbrain (rhombomeres 4-6), and spinal cord.
- CRABP co-localized with RA in these developing embryonic structures.
- Retinol and CRBP distribution was more widespread, with specific expression in surface ectoderm, gut epithelium, and myocardium.
Conclusions:
- RA and CRABP are precisely localized in key developmental regions, including neural crest-derived tissues and the CNS.
- These findings support a significant role for RA in the pattern formation of the craniofacial region and hindbrain.
- RA may function as a morphogen during early embryonic development, similar to its proposed role in limb development.