Haploinsufficiency of Homeodomain Proteins Six3, Vax1, and Otx2, Causes Subfertility in Mice Via Distinct Mechanisms.

Haploinsufficiency occurs when loss of one copy of a diploid gene (hemizygosity) causes a phenotype. It is relatively rare, in that most genes can produce sufficient mRNA and protein from a single copy to prevent any loss of normal activity and function. Reproduction is a complex process relying on migration of GnRH neurons from the olfactory placode to the hypothalamus during development. We have studied three different homeodomain genes Otx2, Vax1, and Six3, and found that deletion of one allele for any of these genes in mice produces subfertility or infertility in one or both sexes, despite the presence of one intact allele. All three heterozygous mice have reduced numbers of GnRH neurons but the mechanisms of subfertility differ significantly. This review compares the subfertility phenotypes and their mechanisms.