Diversification of Hox gene function as a consequence of evolution in cis-regulator sequences.

Hox genes are recognized for their universal role in patterning the antero-posterior (A-P) axis of metazoan embryos. Hox gene expression along the A-P axis occurs in a colinear fashion that reflects the chromosomal position of each gene, suggesting an evolutionary conservation for the function of Hox genes. In vertebrates, 39 Hox genes, distributed in four linkage groups on four chromosomes have been identified. Genes within the individual linkage groups are categorized based on similarities in sequence and expression pattern and are known as paralogs. The work contained in this dissertation demonstrates that evolutionary changes in the cis-regulatory sequences are responsible for the different functions of the murine paralogs Hoxa3 and Hoxd3. The proteins encoded by these two loci can perform equivalent functions during murine development, suggesting an evolutionary selection of functional equivalence. These findings support previous analyses suggesting a quantitative interaction between these proteins during murine development. Finally, analysis of animals lacking function of Hoxb8 has revealed a behavioral phenotype characterized by excessive autogrooming. Grooming behaviors are represented in nearly every animal species, suggesting that it is an evolutionarily ancient behavior. Examination of Hoxb8 mutants did not reveal any morphological abnormalities. Rather, a novel expression pattern for Hoxb8 in the developing and adult central nervous system (CNS) is described. This expression pattern localizes to neuroanatomical structures that have previously been shown to regulate grooming behaviors in rodents. These studies suggest that Hoxb8 has evolved a function beyond embryogenesis.