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Regulation of AP-2 and apoptosis in developing eye in a vitamin A-deficiency model
Jian Zhou1, Devendra M Kochhar
1Department of Pathology, Anatomy, and Cell Biology, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
Background:
Eye malformations induced by vitamin A deficiency (VAD) during pregnancy is a major part of the VAD syndrome. But the signaling role of retinoic acid (RA) in ocular tissues is poorly understood. The goal of this study was to determine the role of retinoic acid receptor (RAR) in the development of eye and the possible signaling pathway.
Methods:
Time-pregnant mice were treated with 1 mg/kg dose of RAR antagonist AGN193109 (AGN) on 8 days postcoitum (dpc). Newborn mice and 18-dpc embryos were used for phenotype studies. Embryonic eyes of 18 dpc were sectioned for histological study. With immunohistochemistry and TUNEL method, we monitored the alternation of AP-2 expression and apoptotic cells in sections of 12- to 18-dpc embryos.
Results:
Treatment with AGN resulted in severe craniofacial and eye malformations in virtually all exposed fetuses. The ocular abnormalities included severe defects in anterior segments such as focal corneal thickening and eversion, absence of corneal endothelium and anterior chamber, differentiation defects of lens, as well as defects in posterior segment such as persistent hyperplastic primary vitreous and retinal eversions. The percentage of AP-2-positive cells in ocular tissues on 12, 14, and 18 dpc was significantly (P < 0.05) reduced in AGN-treated eyes compared to control ones. Additionally, the number of apoptotic cell was significantly (P < 0.05) increased in AGN-treated eyes.
Conclusions:
The blocking of RAR function can lead to ocular abnormalities that depict partial phenocopies of vitamin A-deficiency syndrome. Both an inhibition of expression of AP-2 and an enhancement of cell death contribute to AGN-induced ocular defects.
Insights
Blocking retinoic acid receptor (RAR) function in pregnant mice caused severe eye malformations in offspring. This research clarifies RAR's role in eye development and identifies inhibited AP-2 expression and increased cell death as key factors.
Area of Science:
- Developmental biology
- Ophthalmology
- Genetics
Background:
- Vitamin A deficiency (VAD) during pregnancy causes VAD syndrome with eye malformations.
- The specific signaling role of retinoic acid (RA) in ocular tissues remains unclear.
Purpose of the Study:
- To investigate the role of retinoic acid receptor (RAR) in eye development.
- To elucidate the potential signaling pathways involved in RA-mediated ocular development.
Main Methods:
- Pregnant mice were administered an RAR antagonist (AGN193109) on day 8 postcoitum.
- Phenotypic analysis was performed on newborn mice and 18-day postcoitum embryos.
- Immunohistochemistry and TUNEL assays were used to assess AP-2 expression and apoptosis in embryonic ocular tissues.
Main Results:
- RAR antagonism led to severe craniofacial and ocular malformations, including anterior segment defects (corneal thickening, absent anterior chamber) and posterior segment defects (persistent hyperplastic primary vitreous).
- A significant reduction in AP-2-positive cells and a significant increase in apoptotic cells were observed in the eyes of antagonist-treated embryos.
- Ocular abnormalities mimicked aspects of vitamin A deficiency syndrome.
Conclusions:
- RAR function is critical for normal eye development.
- Inhibition of RAR signaling disrupts ocular development through decreased AP-2 expression and increased apoptosis.
- RAR antagonism provides a model for studying VAD-induced ocular defects.