TARGETED DISRUPTION OF HOXC-4 CAUSES ESOPHAGEAL DEFECTS AND VERTEBRALTRANSFORMATIONS

Mice carrying a nonfunctional allele of hoxc-4 have been generated by gene targeting. The phenotype of mice homozygous for this mutation is strikingly different from those reported in mice lacking the paralogou s genes hoxa-4, hoxb-4 and hoxd-4. In contrast to the mutants of the p aralogous family members, hoxc-4 homozygotes do not manifest abnormali ties in the cervical vertebrae, but instead show vertebral defects tha t extend from the second thoracic vertebra (t2) to t11. Therefore, def ects do not correspond to the anterior limit of expression of hoxc-4 b ut rather begin within the region of strong hoxc-4 expression in the p revertebral anlagen (i.e., pv7-14). While boxed mutant homozygotes tha t reach adulthood are fertile and appear outwardly normal, most die be fore weaning age. The high lethality appears to result from partial or complete blockage of the lumen of the esophagus over a large portion of its length, as well as disorganization of the esophageal musculatur e. Although the Drosophila homolog of hoxc-4 Deformed, is autoregulate d, mutation of the hoxc-4 gene does not affect transcription of its pa ralogous family members. However, in hoxc-4 mutant embryos, transcript ion of both the hoxc-5 and hoxc-6 genes is altered. Employment of cis/ trans analysis showed that the hoxc-4 mutation acts in cis to affect t he pattern of hoxc-5 expression. Therefore, this mutation is likely to cause a reduction of hoxc-5 function as well as complete loss of boxe d function. (C) 1996 Academic Press, Inc.