Targeted Disruption ofhoxc-4Causes Esophageal Defects and Vertebral Transformations

AbstractMice carrying a nonfunctional allele ofhoxc-4have been generated by gene targeting. The phenotype of mice homozygous for this mutation is strikingly different from those reported in mice lacking the paralogous geneshoxa-4, hoxb-4,andhoxd-4.In contrast to the mutants of the paralogous family members,hoxc-4homozygotes do not manifest abnormalities in the cervical vertebrae, but instead show vertebral defects that extend from the second thoracic vertebra (t2) to t11. Therefore, defects do not correspond to the anterior limit of expression ofhoxc-4,but rather begin within the region of stronghoxc-4expression in the prevertebral anlagen (i.e., pv7–14). Whilehoxc-4mutant homozygotes that reach adulthood are fertile and appear outwardly normal, most die before 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 musculature. Although theDrosophilahomolog ofhoxc-4, Deformed,is autoregulated, mutation of thehoxc-4gene does not affect transcription of its paralogous family members. However, inhoxc-4mutant embryos, transcription of both thehoxc-5andhoxc-6genes is altered. Employment of cis/trans analysis showed that thehoxc-4mutation acts in cis to affect the pattern ofhoxc-5expression. Therefore, this mutation is likely to cause a reduction ofhoxc-5function as well as complete loss ofhoxc-4function