TARGETED DISRUPTION OF THE MOUSE HOMOLOG OF THE DROSOPHILA POLYHOMEOTIC GENE LEADS TO ALTERED ANTEROPOSTERIOR PATTERNING AND NEURAL CREST DEFECTS

The rae28 gene is a mouse homologue of the Drosophila polyhomeotic gen e (Nomura, M., Takihara, Ir. and Shimada, K. (1994) Differentiation 57 , 39-50), which is a member of the Polycomb group (Pc-G) of genes (DeC amillis, M., Cheng, N., Pierre, D. and Brock, H.W. (1992) Genes Del? 6 , 223-232). The Pc-G genes are required for the correct expression of the Homeotic complex genes and segment specification during Drosophila embryogenesis and larval development. To study the role of the rae28 gene in mouse development, we generated rae28-deficient mice by gene t argeting in embryonic stem cells. The rae28(-/-) homozygous mice exhib ited perinatal lethality, posterior skeletal transformations and defec ts in neural crest-related tissues, including ocular abnormalities, cl eft palate, parathyroid and thymic hypoplasia and cardiac anomalies. T he anterior boundaries of Hoxa-3, a-4, a-5, b-3, b-4 and d-4 expressio n were shifted rostrally in the paraxial mesoderm of the rae28(-/-) ho mozygous embryos, and those of Hoxb-3 and b-4 expression were also sim ilarly altered in the rhombomeres and/or pharyngeal arches. These alte red Hox codes were presumed to be correlated with the posterior skelet al transformations and neural crest defects observed in the rae28(-/-) homozygous mice. These results indicate that the rae28 gene is involv ed in the regulation of Hox gene expression and segment specification during paraxial mesoderm and neural crest development.