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Alterations in migrating cranial neural crest cells in embryos of mice fed retinoic acid
1Department of Anatomy (1st Division), Kiniki University School of Medicine, Osaka, Japan.
Abstract:
Alterations in migrating neural crest cells induced by all-trans retinoic acid (RA) were studied morphologically and immunohistochemically in the cranial portion of 8-day-old mouse embryos which were derived from dams given 60, 40 or 0 mg kg of RA and killed 2 to 8 h later. Additionally, the embryos exposed to 4 mg/kg of actinomycin D (AD) on day 8 of gestation for 5 h were examined similarly. Light microscopy revealed that RA was cytotoxic and caused the appearance of pleomorphic nuclei, extra-large nucleoli and cytoplasmic budding which replaced lamellipodia and spike-like projections. Electron microscopy revealed pleomorphic nuclei containing nucleoli with major granular portions frequently surrounded with heterochromatin, monosomes, and phagosomes. A monosomal distribution pattern was different from that seen in the neural crest cells exposed to AD. The latter showed incomplete polyribosomal dispersion with fewer nucleolar components. Fewer neural crest cells with choline acetyltransferase-like immunoreactivity were detected in RA- and AD-exposed embryos than in the controls. These findings suggest that excess RA inhibits acetylcholine synthesis of the migrating neural crest cells, in a manner different from AD, and that it enhances phagocytosis. These phenomena modify the characteristics of neural crest cells resulting in craniofacial malformations.
Insights
Excess all-trans retinoic acid (RA) exposure alters migrating neural crest cells, inhibiting acetylcholine synthesis and enhancing phagocytosis, leading to craniofacial malformations in mouse embryos.
Area of Science:
- Developmental biology
- Toxicology
- Neuroscience
Background:
- Neural crest cells are crucial for craniofacial development.
- Retinoic acid (RA) is a critical signaling molecule in embryonic development.
- Exposure to teratogens can cause significant developmental abnormalities.
Purpose of the Study:
- To investigate the morphological and immunohistochemical effects of all-trans retinoic acid (RA) on migrating cranial neural crest cells.
- To compare the effects of RA with actinomycin D (AD) on neural crest cell characteristics.
- To understand the mechanisms by which RA induces craniofacial malformations.
Main Methods:
- Morphological analysis using light and electron microscopy on mouse embryos exposed to RA or AD.
- Immunohistochemical detection of choline acetyltransferase-like immunoreactivity.
- Dosage-dependent administration of RA (60, 40, 0 mg/kg) and a single dose of AD (4 mg/kg).
Main Results:
- RA induced cytotoxicity in neural crest cells, characterized by nuclear and cytoplasmic alterations.
- RA exposure led to changes in nucleolar structure and a distinct monosomal distribution pattern compared to AD.
- Reduced choline acetyltransferase-like immunoreactivity was observed in both RA- and AD-exposed embryos, suggesting inhibited acetylcholine synthesis.
Conclusions:
- Excess RA inhibits acetylcholine synthesis in migrating neural crest cells via a mechanism distinct from AD.
- RA enhances phagocytosis within neural crest cell populations.
- These cellular alterations induced by RA contribute to the development of craniofacial malformations.