Role of Hoxb13 in caudal axis patterning and prostate development

Vertebrate Hox genes encode a family of homeobox transcription factors that regulate developmental programs and determine the embryonic body plan. These functions have largely been determined by the generation of loss-of-function mutations in vertebrate Hox genes through gene targeting technology in mice. Hoxb13 is the last Hox gene to be identified. It is located 5' of Hoxb9 within the HoxB cluster and is expressed in the posterior regions of the developing embryo, including the tail bud and genital tubercule. Loss-of-function mutations of Hoxb13 have not been reported, and the function of this gene was unknown prior to the work outlined herein. This dissertation describes the generation of Hoxb13 null mice and the analyses of mutants that lack Hoxb13 function. Hoxb13 homozygous mutants have an aberrant developmental program in the structures that are derived from the process of secondary neurulation which include the caudal vertebrae within the tail, the caudal spinal ganglia, and the secondary neural tube. The phenotype is novel for Hox gene mutant phenotypes in that all of the aforementioned structures display an overgrowth phenotype, and further analyses in the secondary neural tube reveals that the phenotypes are caused by both over-proliferation of cells and failure of the normal apoptotic pathway that removes the secondary neural tube. This dissertation also addresses the function of Hoxb13 in adults. In contrast to its role in limiting growth during development, Hoxb13 also determines a pathway that is specific to the prostatic luminal epithelium ventral lobe. Hoxb13 homozygous mutants do not secrete the ventral prostate specific secretory proteins including p12, a serine protease inhibitor, and p25, a spermine binding protein. Additionally, homozygote mutant ventral prostates secrete polymeric immunoglobulin receptor (pIgR) and androgen binding protein (ABP), which are not normally secreted by the prostate, indicating that the homozygous mutant prostate luminal cells have lost identity. In addition to losing identity, homozygous mutant ventral prostate luminal cells lose polarity, as indicated by the expression of basal cell markers on the apical surface of luminal cells. This dissertation provides analyses of both the developmental and adult functions of Hoxb13 and underscores how a Hox gene that has a very specific function in embryonic patterning can be later recruited for very different functions in adult tissues.