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Development, Vol 122, Issue 12 3817-3828, Copyright © 1996 by Company of Biologists
JOURNAL ARTICLES |
JR Barrow and MR Capecchi
Howard Hughes Medical Institute, Department of Human Genetics, University of Utah, School of Medicine, Salt Lake City 84112, USA.
Mice with a disruption in the hoxb-2 locus were generated by gene targeting. 75% of the hoxb-2 mutant homozygotes died within 24 hours of birth. While a majority of these mice had severe sternal defects that compromised their ability to breathe, some had relatively normal sternum morphology, suggesting that one or more additional factor(s) contributed to neonatal lethality. At 3-3.5 weeks of age, half of the remaining hoxb-2 homozygotes became weak and subsequently died. All of the mutants that survived to 3 weeks of age showed marked facial paralysis similar to, but more severe than, that reported for hoxb-1 mutant homozygotes (Goddard, J. M., Rossel, M., Manley, N. R. and Capecchi, M. R. (1996) Development 122, 3217-3228). As for the hoxb-1 mutations, the facial paralysis observed in mice homozygous for the hoxb-2 mutation results from a failure to form the somatic motor component of the VIIth (facial) nerve which controls the muscles of facial expression. Features of this phenotype closely resemble the clinical signs associated with Bell's Palsy and Moebius Syndrome in humans. The sternal defects seen in hoxb-2 mutant mice are similar to those previously reported for hoxb-4 mutant mice (Ramirez-Solis, R., Zheng, H., Whiting, J., Krumlauf, R. and Bradley. A. (1993) Cell 73, 279-294). The above results suggest 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. Consistent with this proposal, we found that the hoxb-2 mutation disrupts the expression of hoxb-1 in cis. In addition, the hoxb-2 mutation changes 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.
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