Dax1 modulates ERα-dependent hypothalamic estrogen sensing in female mice

Jose M. Ramos-Pittol, Isabel Fernandes-Freitas, Alexandra Milona, Stephen M. Manchishi, Kara Rainbow, Brian Y. H. Lam, John A. Tadross, Anthony Beucher, William H. Colledge, Inês Cebola, Kevin G. Murphy, Irene Miguel-Aliaga, Giles S. H. Yeo, Waljit S. Dhillo () and Bryn M. Owen ()
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Jose M. Ramos-Pittol: University of Innsbruck
Isabel Fernandes-Freitas: Imperial College London
Alexandra Milona: Imperial College London
Stephen M. Manchishi: Cambridge University
Kara Rainbow: Cambridge University
Brian Y. H. Lam: Cambridge University
John A. Tadross: Cambridge University
Anthony Beucher: Imperial College London
William H. Colledge: Cambridge University
Inês Cebola: Imperial College London
Kevin G. Murphy: Imperial College London
Irene Miguel-Aliaga: Imperial College London
Giles S. H. Yeo: Cambridge University
Waljit S. Dhillo: Imperial College London
Bryn M. Owen: Imperial College London

Nature Communications, 2023, vol. 14, issue 1, 1-10

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-38618-y

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