TRANSCRIPTIONAL INTERFERENCES AT THE HOXA4 HOXA5 LOCUS - IMPORTANCE OF CORRECT HOXA5 EXPRESSION FOR THE PROPER SPECIFICATION OF THE AXIAL SKELETON/

We have previously described a Hoxa5 mutant mouse line in which specif ication of axial identity is perturbed and viability is markedly reduc ed. In the present study, we assay the Hoxa5 mutation in different gen etic backgrounds and carry out a complete analysis of skeletal transfo rmations. Although Hoxa5 is expressed over a large domain during embry ogenesis, homeotic transformations of the axial skeleton are confined between cervical vertebra C3 and thoracic vertebra T2, which correspon ds to the specific expression domain of the major Hoxa5 transcript. Lo ss of Hoxa5 function also affects the formation of the acromion in the appendicular skeleton, Disruption of the adjacent Hoxa4 gene leads to similar homeotic transformations of the cervicothoracic vertebrae. To discriminate the respective role of each gene, we generated transhete rozygous animals carrying inactivated Hoxa4 and Hoxa5 alleles on diffe rent chromosomes. Compound heterozygous mutants exhibit homeotic trans formations in the cervicothoracic transition region more reminiscent t o those observed in Hoxa5 homozygous mutants. Although the Hoxa5 mutat ion does not significantly affect Hoxa4 expression, the pattern of Hox a5 expression is impaired in cis by the Hoxa4 mutation, specifically i n the cervicothoracic region of the prevertebral column. The expressio n of Hoxa5 in this particular domain is also perturbed by the Hoxa5 mu tation itself, raising the possibility off regional autoregulation, Al together, these results demonstrate the crucial role of Hoxa5 in the s pecification of the cervical and upper thoracic region of the skeleton and establish the importance of its correct expression for the proper patterning of the embryo. (C) 1998 Wiley-Liss, Inc.