TARGETED DISRUPTION OF THE HOXB-2 LOCUS IN MICE INTERFERES WITH EXPRESSION OF HOXB-1 AND HOXB-4

Mice with a disruption in the hoxb-2 locus were generated by gene targ eting, 75% of the hoxb-2 mutant homozygotes died within 24 hours of bi rth, While a majority of these mice had severe sternal defects that co mpromised their ability to breathe, some had relatively normal sternum morphology, suggesting that one or more additional factor(s) contribu ted to neonatal lethality, At 3-3.5 weeks of age, half of the remainin g hoxb-2 homozygotes became weak and subsequently died. All of the mut ants that survived to 3 weeks of age showed marked facial paralysis si milar to, but more severe than, that reported for hoxb-1 mutant homozy gotes (Goddard, J. M., Rossel, M., Manley, N. R. and Capecchi, M. R. ( 1996) Development 122, 3217-3228). As for the hoxb-1 mutations, the fa cial paralysis observed in mice homozygous for the hoxb-2 mutation res ults from a failure to form the somatic motor component of the VIIth ( facial) nerve which controls the muscles of facial expression, Feature s of this phenotype closely resemble the clinical signs associated wit h Bell's Palsy and Moebius Syndrome in humans, The sternal defects see n in hoxb-2 mutant mice are similar to those previously reported for h oxb-4 mutant mice (Ramirez-Solis, R., Zheng, H., Whiting, J., Krumlauf , R. and Bradley. A. (1993) Cell 73, 279-294). The above results sugge st that the hoxb-2 mutant phenotype may result in part from effects of the hoxb-2 mutation on the expression of both hoxb-1 and hoxb-4. Cons istent with this proposal, we found that the hoxb-2 mutation disrupts the expression of hoxb-1 in cis, In addition, the hoxb-2 mutation chan ges the expression of hoxb-4 and the hoxb-4 mutation, in turn, alters the pattern of hoxb-2 expression, Hoxb-2 and hoxb-4 appear to function together to mediate proper closure of the ventral thoracic body wall, Failure in this closure results in severe defects of the sternum.