Dax1 modulates ERα-dependent hypothalamic estrogen sensing in female mice

• Published in: Nature communications 2023-05, Vol.14 (1), p.3076-10, Article 3076
• Main Authors: Ramos-Pittol, Jose M., Fernandes-Freitas, Isabel, Milona, Alexandra, Manchishi, Stephen M., Rainbow, Kara, Lam, Brian Y. H., Tadross, John A., Beucher, Anthony, Colledge, William H., Cebola, Inês, Murphy, Kevin G., Miguel-Aliaga, Irene, Yeo, Giles S. H., Dhillo, Waljit S., Owen, Bryn M.
• Format: Article
• Language: English
• Subjects: 38/77; 631/337; 631/378; 631/443/494; 692/163; Animals; Arcuate nucleus; Arcuate Nucleus of Hypothalamus - metabolism; DAX-1 Orphan Nuclear Receptor - genetics; DAX-1 Orphan Nuclear Receptor - metabolism; Developmental stages; Estradiol - metabolism; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Estrogen receptors; Estrogens; Estrogens - metabolism; Female; Females; Fertility; Gametocytes; Gene expression; Genomic analysis; Gonadotropins; Hormones; Humanities and Social Sciences; Hypothalamus; Hypothalamus - metabolism; Kiss1 protein; Kisspeptins - genetics; Kisspeptins - metabolism; Mice; multidisciplinary; Nuclei (cytology); Pituitary; Pituitary (anterior); Pituitary hormones; Receptors; Regulatory sequences; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-38618-y

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. Estrogen controls female fertility in part via restraining or promoting kisspeptin (Kiss1)-neuron activity in the arcuate hypothalamic nucleus and the AVPV hypothalamic nucleus, respectively. Here the authors report that estrogen receptor alpha (ERα) interacts with the genome and the nuclear receptor co-repressor NR0B1 (DAX1) to manifest region-specific actions on Kiss1 expression.