AP-2-NULL CELLS DISRUPT MORPHOGENESIS OF THE EYE, FACE, AND LIMBS IN CHIMERIC MICE

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 a bnormalities observed in the knockout mouse suggested that AP-2 may re gulate several morphogenic pathways. To uncouple the individual develo pmental mechanisms that are dependent on AP-2, we have now analyzed ch imeric mice composed of both wild-type and AP-2-null cells. The phenot ypes obtained from these chimeras indicate that there is an independen t 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 r ole for AP-2 that was masked previously in the knockout mice. Furtherm ore, we also have uncovered an unexpected influence of AP-2 on limb pa ttern formation; this influence is typified by major limb duplications . The range of phenotypes observed in the chimeras displays a signific ant overlap with those caused by teratogenic levels of retinoic acid, strongly suggesting that AP-2 is an important component of the mechani sm of action of this morphogen.