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Updated: Dec 29, 2025
Analysis of Retinoic Acid-induced Neural Differentiation of Mouse Embryonic Stem Cells in Two and Three-dimensional Embryoid Bodies
Published on: April 22, 2017
Teratogenic effects of retinoic acid are modulated in mice lacking expression of epidermal growth factor and
Barbara D Abbott1, Deborah S Best, Michael G Narotsky
1Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, 2525 East Highway 54, Durham, NC 27713, USA. Abbott.barbara@epa.gov
Background:
Epidermal growth factor (EGF) and transforming growth factor-alpha (TGFalpha) regulate cell proliferation and differentiation in the embryo. The induction of cleft palate (CP) by all trans-retinoic acid (RA) was associated with altered expression of TGFalpha, EGF receptor, and binding of EGF. This study uses knockout (KO) mice to examine the roles of EGF and TGFalpha in teratogenic responses of embryos exposed to RA.
Methods:
Pregnant wild-type (WT) mice of mixed genetic background, EGF KO, C57BL/6J, and TGFalpha KO mice were given a single oral dose of RA (100 mg/kg, 10 ml/kg) or corn oil on GD 10 at 12 PM, GD 11 at 12 PM or 4 PM, or GD 12 at 8 AM or 12 PM (plug day = GD 0). GD 18 fetuses were examined for external, visceral, and skeletal effects.
Results:
After exposure to RA on GD 12, the incidence of CP in EGF KO was significantly reduced relative to WT. In TGFalpha KO fetuses, RA exposure on GD 10 increased the incidence of CP versus C57BL/6J. The incidence of skeletal defects in the limbs, vertebrae, sternebrae, and ribs were also affected by lack of expression of EGF or TGFalpha with region-specific amelioration or exacerbation of the effects of RA. In TGFalpha KO fetuses, incidences of forelimb long bone and digit defects increased relative to C57BL/6J. In EGF KO fetuses, relative to WT, the incidence of hindlimb oligodactyly was increased. In EGF KO, but not WT, RA produced short, bent radius, humerus, and ulna. Both TGFalpha and EGF KO mice had increased incidences of dilation of the renal pelvis and this was reduced by RA.
Conclusions:
RA exposure produced skeletal and visceral defects in all genotypes; however, EGF or TGFalpha KO influenced the incidence and severity of defects. This study supports a role for EGF and TGFalpha in the response to RA.
Insights
This study reveals that knockout mice lacking epidermal growth factor (EGF) or transforming growth factor-alpha (TGFalpha) show altered susceptibility to retinoic acid (RA)-induced birth defects, highlighting their crucial roles in embryonic development and teratogenic responses.
Area of Science:
- Developmental Biology
- Teratology
- Genetics
Background:
- Epidermal growth factor (EGF) and transforming growth factor-alpha (TGFalpha) are critical regulators of embryonic cell proliferation and differentiation.
- Retinoic acid (RA) is a known teratogen that can induce birth defects, including cleft palate (CP).
- Previous studies suggest a link between RA-induced CP and altered expression of TGFalpha, EGF, and their receptor.
Purpose of the Study:
- To investigate the specific roles of EGF and TGFalpha in mediating the teratogenic effects of RA during embryonic development.
- To determine how the absence of EGF or TGFalpha influences the incidence and severity of RA-induced skeletal and visceral malformations.
Main Methods:
- Wild-type (WT), EGF knockout (KO), and TGFalpha KO mice were exposed to a single oral dose of RA or a control vehicle on specific days of gestation (GD 10-12).
- Fetal outcomes were assessed on GD 18 for external, visceral, and skeletal abnormalities.
- Genetic background of mice included mixed background and C57BL/6J.
Main Results:
- RA exposure induced skeletal and visceral defects across all genotypes.
- EGF KO mice exhibited a reduced incidence of RA-induced cleft palate when exposed on GD 12 compared to WT.
- TGFalpha KO mice showed an increased incidence of CP with RA exposure on GD 10 and increased limb/digit defects.
- Both EGF and TGFalpha KO mice displayed altered incidences of skeletal defects (limbs, vertebrae, sternebrae, ribs) and renal pelvis dilation, with varying amelioration or exacerbation of RA's effects.
Conclusions:
- EGF and TGFalpha play significant, genotype-dependent roles in modulating the teratogenic effects of RA.
- The findings support the involvement of EGF and TGFalpha signaling pathways in the embryonic response to RA exposure.
- Targeting these pathways could offer insights into preventing or mitigating RA-induced developmental abnormalities.
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