MUTATIONS IN PARALOGOUS HOX GENES RESULT IN OVERLAPPING HOMEOTIC TRANSFORMATIONS OF THE AXIAL SKELETON - EVIDENCE FOR UNIQUE AND REDUNDANT FUNCTION

Hoxd-4 (previously known as Hox-4.2 and -5.1) is a mouse homeobox-cont aining gene homologous to the Drosophila homeotic gene Deformed. Durin g embryogenesis, Hoxd-4 is expressed in the presumptive hindbrain and spinal cord, prevertebrae, and other tissues. In the adult, Hoxd-4 tra nscripts are expressed predominantly in the testis and kidney, and to a lesser extent in intestine and heart. To understand the role of Hoxd -4 during mouse embryogenesis, we generated Hoxd-4 mutant mice. Mice h eterozygous or homozygous for the Hoxd-4 mutation exhibit homeotic tra nsformations of the second cervical vertebrae (C2) to the first cervic al vertebrae (C1) and malformations of the neural arches of C1 to C3 a nd of the basioccipital bone. The phenotype was incompletely penetrant and showed variable expressivity on both an F2 hybrid and 129 inbred genetic background. The mutant phenotype was detected in the cartilagi nous skeleton of 14.5-day (E14.5) mutant embryos but no apparent diffe rences were detected in the somites of E9.5 mutant embryos, suggesting that the abnormalities develop after E9.5 perhaps during or after res egmentation of the somites to form the prevertebrae. These results sug gest that Hoxd-4 plays a role in conferring position information along the anteroposterior axis in the skeleton. The phenotypic similarities and differences between Hoxd-4 and previously reported Hoxa-4 and Hox b-4 mutant mice suggest that Hox gene paralogs have both redundant and unique functions. (C) 1995 Academic Press, Inc.