UC San Diego

Idiopathic Hypogonadal Hypogonadism (IHH), a condition associated with the loss of gonadotropin releasing hormone (GnRH) neurons and/or disruption of the hypothalamic pituitary gonadal axis (HPG), leads to complete infertility and abnormal reproduction. Currently, a large number of the mutations involved with IHH are of unknown origin, but are likely to arise from polygenic mutations. We here describe Ventral Anterior Homoebox 1 (Vax1) as a potential genetic contributor to IHH. Vax1 heterozygote mice show numerous characteristics related to subfertility including smaller litters, delayed estrous cycling in females, and reduced sperm quality in males. The importance of GnRH neurons for reproduction and development led us to investigate the regulatory role of Vax1 in GnRH transcription, which determined Vax1's ability to repress GnRH transcription through the -41bp binding site of the GnRH promoter. cFos, an immediate early gene, has been known to repress GnRH transcription through AP-1 sites on the GnRH promoter. The possible interaction between Vax1 and cFos was also considered to further determine the molecular mechanism of Vax1 regulated repression of the GnRH promoter