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AP-2-null cells disrupt morphogenesis of the eye, face, and limbs in chimeric mice
T Nottoli1, S Hagopian-Donaldson, J Zhang
1Department of Molecular, Cellular, and Developmental Biology, Yale University, 266 Whitney Avenue, New Haven, CT 06511, USA.
Abstract:
The homozygous disruption of the mouse AP-2 gene yields a complex and lethal phenotype that results from defective development of the neural tube, head, and body wall. The severe and pleiotropic developmental abnormalities observed in the knockout mouse suggested that AP-2 may regulate several morphogenic pathways. To uncouple the individual developmental mechanisms that are dependent on AP-2, we have now analyzed chimeric mice composed of both wild-type and AP-2-null cells. The phenotypes obtained from these chimeras indicate that there is an independent requirement for AP-2 in the formation of the neural tube, body wall, and craniofacial skeleton. In addition, these studies reveal that AP-2 exerts a major influence on eye formation, which is a critical new role for AP-2 that was masked previously in the knockout mice. Furthermore, we also have uncovered an unexpected influence of AP-2 on limb pattern formation; this influence is typified by major limb duplications. The range of phenotypes observed in the chimeras displays a significant overlap with those caused by teratogenic levels of retinoic acid, strongly suggesting that AP-2 is an important component of the mechanism of action of this morphogen.
Insights
The AP-2 gene is crucial for embryonic development, impacting neural tube, head, and body wall formation. Chimeric mice reveal AP-2
Area of Science:
- Developmental Biology
- Genetics
- Molecular Biology
Background:
- Homozygous disruption of the mouse AP-2 gene leads to lethal developmental defects.
- Observed abnormalities suggested AP-2 regulates multiple morphogenic pathways.
- Previous studies in knockout mice masked some AP-2 functions due to lethality.
Purpose of the Study:
- To investigate the independent roles of AP-2 in specific developmental processes.
- To identify novel functions of AP-2 masked in homozygous knockout models.
- To explore the relationship between AP-2 and retinoic acid signaling in development.
Main Methods:
- Generation and analysis of chimeric mice composed of wild-type and AP-2-null cells.
- Phenotypic analysis of developmental abnormalities in chimeric mice.
Main Results:
- AP-2 is independently required for neural tube, body wall, and craniofacial skeleton formation.
- AP-2 plays a significant role in eye development, a function previously obscured.
- AP-2 influences limb pattern formation, causing duplications, and overlaps with retinoic acid effects.
Conclusions:
- AP-2 is essential for multiple, independent developmental processes.
- AP-2 has critical roles in eye and limb development.
- AP-2 is likely involved in the mechanism of action of retinoic acid as a morphogen.