Boulet A M, Capecchi M R
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, 84112, USA.
Dev Biol. 1996 Jul 10;177(1):232-49. doi: 10.1006/dbio.1996.0159.
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 paralogous genes hoxa-4, hoxb-4, and hoxd-4. In contrast to the mutants of the paralogous family members, hoxc-4 homozygotes 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 of hoxc-4, but rather begin within the region of strong hoxc-4 expression in the prevertebral anlagen (i.e., pv7-14). While hoxc-4 mutant 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 the Drosophila homolog of hoxc-4, Deformed, is autoregulated, mutation of the hoxc-4 gene does not affect transcription of its paralogous family members. However, in hoxc-4 mutant embryos, transcription of both the hoxc-5 and hoxc-6 genes is altered. Employment of cissolidustrans analysis showed that the hoxc-4 mutation acts in cis to affect the pattern of hoxc-5 expression. Therefore, this mutation is likely to cause a reduction of hoxc-5 function as well as complete loss of hoxc-4 function.
通过基因靶向技术已培育出携带hoxc - 4无功能等位基因的小鼠。该突变纯合子小鼠的表型与缺乏同源基因hoxa - 4、hoxb - 4和hoxd - 4的小鼠所报道的表型显著不同。与同源家族成员的突变体不同，hoxc - 4纯合子在颈椎中未表现出异常，而是显示出从第二胸椎（t2）到t11的椎体缺陷。因此，缺陷并不对应于hoxc - 4表达的前界，而是始于椎前原基中hoxc - 4强表达区域内（即pv7 - 14）。虽然成年的hoxc - 4突变纯合子可育且外观正常，但大多数在断奶前死亡。高致死率似乎是由于食管大部分长度的管腔部分或完全阻塞以及食管肌肉组织紊乱所致。尽管hoxc - 4的果蝇同源物Deformed是自我调节的，但hoxc - 4基因的突变并不影响其同源家族成员的转录。然而，在hoxc - 4突变胚胎中，hoxc - 5和hoxc - 6基因的转录均发生改变。采用顺式分析表明，hoxc - 4突变以顺式作用影响hoxc - 5的表达模式。因此，该突变可能导致hoxc - 5功能降低以及hoxc - 4功能完全丧失。
