Dax1 modulates ERα-dependent hypothalamic estrogen sensing in female mice
José M. Ramos Pittol, Isabel Fernandes-Freitas, Alexandra Milona, Stephen M. Manchishi, Kara Rainbow, Brian Lam, John A. Tadross, Anthony Beucher, William H Colledge, Inês Cebola, Kevin G. Murphy, Irene Miguel‐Aliaga, Giles S.H. Yeo, Waljit S. Dhillo, Bryn M. Owen
Abstract
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 (ERα) 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 ERα may control the KISS1-neuron, and Kiss1 gene expression, to couple gonadotropin release to the developmental stage of the oocyte.