Dax1 modulates ER alpha-dependent hypothalamic estrogen sensing in female mice

Coupling the release of pituitary hormones to the developmental stage of the oocyte is essential for female fertility. It requires estrogen to restrain kisspeptin (KISS1)-neuron pulsatility in the arcuate hypothalamic nucleus, while also exerting a surge-like effect on KISS1-neuron activity in the AVPV hypothalamic nucleus. However, a mechanistic basis for this region-specific effect has remained elusive. Our genomic analysis in female mice demonstrate that some processes, such as restraint of KISS1-neuron activity in the arcuate nucleus, may be explained by region-specific estrogen receptor alpha (ER alpha) DNA binding at gene regulatory regions. Furthermore, we find that the Kiss1-locus is uniquely regulated in these hypothalamic nuclei, and that the nuclear receptor co-repressor NR0B1 (DAX1) restrains its transcription specifically in the arcuate nucleus. These studies provide mechanistic insight into how ER alpha may control the KISS1-neuron, and Kiss1 gene expression, to couple gonadotropin release to the developmental stage of the oocyte.

Automated summary

Coupling the release of pituitary hormones to the developmental stage of the oocyte is crucial for female fertility. In this study, the researchers found that estrogen plays a role in restraining and activating different regions of the hypothalamus to control the activity of KISS1-neuron and the expression of Kiss1 gene. These findings provide mechanistic insights into how estrogen regulates fertility in females.