HOX genes: seductive science, mysterious mechanisms

Abstract

HOX genes are evolutionarily highly conserved. The HOX proteins which they encode are master regulators of embryonic development and continue to be expressed throughout postnatal life. The 39 human HOX genes are located in four clusters (A-D) on different chromosomes at 7p15, 17q21 [corrected] 12q13, and 2q31 respectively and are assumed to have arisen by duplication and divergence from a primordial homeobox gene. Disorders of limb formation, such as hand-foot-genital syndrome, have been traced to mutations in HOXA13 and HOXD13. Evolutionary conservation provides unlimited scope for experimental investigation of the functional control of the Hox gene network which is providing important insights into human disease. Chromosomal translocations involving the MLL gene, the human homologue of the Drosophila gene trithorax, create fusion genes which exhibit gain of function and are associated with aggressive leukaemias in both adults and children. To date 39 partner genes for MLL have been cloned from patients with leukaemia. Models based on specific translocations of MLL and individual HOX genes are now the subject of intense research aimed at understanding the molecular programs involved, and ultimately the design of chemotherapeutic agents for leukaemia. Investigation of the role of HOX genes in cancer has led to the concept that oncology may recapitulate ontology, a challenging postulate for experimentalists in view of the functional redundancy implicit in the HOX gene network.

Fig 1

A representative dendrogram illustrating the evolution of Hox clusters. Hox gene clusters are thought to have developed by a process of duplication and divergence from a primordial homeobox gene estimated to have arisen about 1,000 million years ago.

Fig 2

Conservation between the HOM-C and HOX gene clusters. The four Hox gene clusters found in mammals are conserved from the Drosophila Hom-C complex in terms of nucleotide sequence and colinear expression. During embryonic development, the genes are expressed in a pattern that correlates with the chromosomal positioning, depicted here for human and mouse. The 3′ genes are expressed both earlier and more anteriorly than the 5′ genes.

Fig 3

HOX gene/protein structure and mutations found in limb malformation. (A) HOX genes consist of two exons and one intron. Exon 2 contains a 180-nucleotide sequence, termed the homeobox, that encodes a 60-amino acid helix-turn-helix motif, termed the homeodomain, which has DNA-binding activity. (B) Mutations in HOXA13 and HOXD13 are found in disorders of limb formation, such as hand–foot–genital syndrome (HFGS), synpolydactyly (SPD), and brachydactyly.