UC San Diego

Kisspeptin neurons, located in the anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC) of the hypothalamus, serve as critical regulators of reproduction, mediating puberty onset, ovulation, and pulsatile gonadotropin-releasing hormone/luteinizing hormone (LH) secretion. Homeodomain transcription factors, such as VAX1 and SIX3, have been implicated in fertility, although the role of these proteins in regulating kisspeptin neuron activity and Kiss1 gene expression is unclear. I have demonstrated that VAX1 differentially regulates Kiss1 gene expression in the ARC of male versus female mice and that the loss of Vax1 from kisspeptin neurons results in a reduction of Kiss1-positive cells at the time of the pre-ovulatory LH surge. I have also found that kisspeptin-specific SIX3 is necessary for estrous cyclicity and maximal fecundity in female mice and that SIX3 differentially regulates the mouse and human Kiss1/KISS1 promoters in vitro and can act as repressor of cFos transcription in vitro and in vivo. This work provides context for the specific roles that homeodomain transcription factors play within kisspeptin neurons and their implications in fertility.