INNER-EAR AND MATERNAL REPRODUCTIVE DEFECTS IN MICE LACKING THE HMX3 HOMEOBOX GENE

The Hmx homeobox gene family is of ancient origin, being present in sp ecies as diverse as Drosophila, sea urchin and mammals, The three memb ers of the murine Hmx family, designated Hmx1, Hmx2 and Hmx3, are expr essed in tissues that suggest a common functional role in sensory orga n development and pregnancy, Hmx3 is one of the earliest markers for v estibular inner ear development during embryogenesis, and is also upre gulated in the myometrium of the uterus during pregnancy, Targeted dis ruption of the Hmx3 gene results in mice with abnormal circling behavi or and severe vestibular defects owing to a depletion of sensory cells in the saccule and utricle, and a complete loss of the horizontal sem icircular canal crista, as well as a fusion of the utricle and saccule endolymphatic spaces into a common utriculosaccular cavity. Both the sensory and secretory epithelium of the cochlear duct appear normal in the Hmx3 null animals, The majority of Hmx3 null females have a repro ductive defect. Hmx3 null females can be fertilized and their embryos undergo normal preimplantation development, but the embryos fail to im plant successfully in the Hmx3 null uterus and subsequently die. Trans fer of preimplantation embryos from mutant Hmx3 uterine horns to wild- type pseudopregnant females results in successful pregnancy, indicatin g a failure of the Hmx3 null uterus to support normal post-implantatio n pregnancy, Molecular analysis revealed the perturbation of Hmx, Wnt and LIF gene expression in the Hmx3 null uterus, Interestingly, expres sion of both Hmx1 and Hmx2 is downregulated in the Hmx3 null uterus, s uggesting a hierarchical relationship among the three Hmx genes during pregnancy.