Hox is in the hair: a break in colinearity?

During mammalian fetal development, axial structures acquire their specifications through the action of the Hox gene family of transcription factors (for review, see Krumlauf 1994). These are 39 such genes that are responsible for giving spatially restricted cues in a variety of embryonic derivatives, from the neural tube to the intestinal tract. In presomitic mesoderm, for example, level-specific qualitative as well as quantitative differences in HOX protein content will instruct the future sclerotomes on the morphological features that particular vertebrae should display. Therefore, it is important that the establishment of Hox expression domains be controlled faithfully, as slight mistakes in this process will lead to the misidentification of the corresponding structures, an effect that is often referred to as homeotic transformation. The complex coordination of this control is achieved, in part, through a unique property of this gene family; genes are organized along the chromosome in a genomic sequence that reflects their time and place of activation during development. In mammals, there are four Hox clusters (A to D) and within each cluster, Hox genes located at the 38 end are activated first and in anterior embryonic domains, whereas genes located at the 58 end are transcribed subsequently and in more caudal areas. The spatial aspect of this intriguing correspondence, or ‘‘colinearity,’’ was described originally by Lewis (1997) in Drosophila, and has since been observed in all animals exhibiting an anterior-to-posterior axial polarity. Interestingly, no clear exception to this rule has been reported to date. In this issue, however, Godwin and Capecchi present some surprising results from an elegant study of murine Hoxc13, a very posterior gene member of the HoxC complex. Unexpectedly, Hoxc13 is expressed in hair follicles throughout the body as well as in vibrissae and in the tongue, that is, at locations much too anterior for the ‘‘genomic position’’ of this gene. Does Hoxc13 violate the code of colinearity? Hox genes members of the most posterior groups of paralogy, from group 9 to 13, are all related to the Drosophila gene Abdominal-B (AbdB; Izpisua-Belmonte et al. 1991). Expression studies as well as gene knock outs have revealed that Hoxd13 and Hoxa13 are required for the development of the most posterior structures in the trunk, such as the sacrocaudal vertebral transition, the anal sphincter, the external genitalia, as well as the urogenital system and associated glands (Dollé et al. 1993; Davis and Capecchi 1996; Kondo et al. 1996, 1997; Podlasek et al. 1996; Warot et al. 1997). The expression of the two other members of this paralogy group, Hoxb13 (Zeltser et al. 1996) and Hoxc13 (Peterson et al. 1994), suggested that a similar posterior restriction would be observed in the phenotypes of mice carrying null alleles of these genes. The generation of mice lacking Hoxc13 function confirmed that alterations of the vertebral column were restricted to the tail, where homeotic transformations of caudal vertebrae toward a more anterior morphology were observed (Godwin and Capecchi 1997). Surprisingly however, homozygous animals lacked vibrissae at birth and subsequently showed a strong defect in brittle hair leading to alopecia, that is, the absence of emerging hairs, although hair follicles seemed to form normally. Because the inactivation strategy involved the insertion of lacZ reporter sequences in-frame with the Hoxc13 coding sequences, a detailed expression study allowed a perfect correlation to be established between this unexpected phenotype and Hoxc13 transcription specificity during fetal skin development.