The known genetic causes of idiopathic hypogonadotropic hypogonadism (IHH) are often associated with the loss of GnRH neurons, leading to the disruption of the hypothalamic pituitary gonadal axis and subfertility. The majority of IHH cases have unknown origins and likely arise from compound mutations in more than one gene. Here we identify the homeodomain transcription factor ventral anterior homeobox1 (Vax1) as a potential genetic contributor to polygenic IHH. Although otherwise healthy, male and female Vax1 heterozygous (HET) mice are subfertile, indicating dosage sensitivity for the Vax1 allele. Although Vax1 mRNA is expressed in the pituitary, hypothalamus, and testis, we did not detect Vax1 mRNA in the sperm, ovary, or isolated pituitary gonadotropes. Whereas Vax1 HET females produced normal numbers of superovulated oocytes, corpora lutea numbers were reduced along with a slight increase in circulating basal LH and estrogen. The subfertility originated in the hypothalamus in which kisspeptin and GnRH transcripts were altered along with a substantial reduction of GnRH neuron number. Although the pituitary responded normally to a GnRH challenge, diestrus females had reduced LHβ and FSHβ in diestrus. Furthermore, Vax1 HET males had reduced GnRH mRNA and neuron numbers, whereas the pituitary had normal transcript levels and response to GnRH. Interestingly, the Vax1 HET males had an 88% reduction of motile sperm. Taken together, our data suggest that Vax1 HET subfertility originates in the hypothalamus by disrupting the hypothalamic-pituitary-gonadal axis. In addition, male subfertility may also be due to an unknown effect of Vax1 in the testis.
