UC San Diego

Infertility has commonly been linked to problems in the gonads, such as the testes or ovaries; however, today it is clear that many cases of subfertility and infertility are caused by issues in the hypothalamus, an important brain structure of the neuroendocrine system that regulates fertility. The gonadotropin-releasing hormone (GnRH) and kisspeptin neurons within the hypothalamus are at the apex of the hypothalamic-pituitary- gonadal (HPG) axis, which controls fertility. Both of these neuronal populations receive input from the suprachiasmatic nucleus (SCN), which incorporates time-of-day information and circadian rhythms into fertility regulation. In this study, we identify a novel transcription factor, Ventral anterior homeobox 1 (VAX1), as a critical regulator of GnRH neuron development and kisspeptin neuron function. Through the use of transgenic mouse models, we deleted Vax1 within the hypothalamus using the synapsincre mouse, allowing deletion of Vax1 in mature neurons. Vax1flox:synapsincre (Vax1syn) females were subfertile, but paradoxically had more GnRH neurons, and normal hormonal levels. To determine what neuronal populations within the hypothalamus were responsible for the subfertility of Vax1syn females, we specifically deleted Vax1 within kisspeptin neurons (Vax1KISS) and arginine vasopressin (AVP) neurons (Vax1AVP), one of the major neuronal populations of the SCN. Both Vax1KISS and Vax1AVP females had delayed first estrus. However, only Vax1KISS had impaired fertility. Thus, Vax1 in AVP and kisspeptin neurons is important in determining first estrus, and Vax1 in kisspeptin neurons is required for normal fertility.