Dax1 modulates ERĪ±-dependent hypothalamic estrogen sensing in female mice.
Published version
Peer-reviewed
Repository URI
Repository DOI
Type
Change log
Authors
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 (ERĪ±) 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 ERĪ± may control the KISS1-neuron, and Kiss1 gene expression, to couple gonadotropin release to the developmental stage of the oocyte.
Description
Acknowledgements: The Section of Endocrinology and Investigative Medicine is funded by grants from the MRC, NIHR and is supported by the NIHR Biomedical Research Centre Funding Scheme and the NIHR/Imperial Clinical Research Facility. This article presents independent research. W.S.D. is funded by an NIHR Research Professorship and an NIHR Senior Investigator Award. This work was supported by a Sir Henry Dale Fellowship jointly funded by The Wellcome Trust and The Royal Society to BMO (105545/Z/14/Z). Grants from the Tyrolean Science Fund to JMRP agreement F.18896. KR and GSHY are supported by the MRC Metabolic Diseases Unit (MC_UU_00014/1). BYHL is supported by a BBSRC Project Grant (BB/S017593/1). JAT is supported by an NIHR Clinical Lectureship (CL-2019-14-504). The Cambridge Brain Bank is supported by the NIHR Cambridge Biomedical Research Centre. SMM was funded by a Commonwealth Scholarship and WHC by the Ford Physiology Fund Endowment. AM and I-MA are supported by MRC intramural funding and ERC Advanced Grant (787470-IntraGutSex). KGM is supported by BBSRC (BB/W001497/1) and DUK (18/0005886, 20/0006295) project grants. IC was an Academy of Medical Sciences Springboard Fellow (SBF005\1050) during this study, the Scheme was supported by the British Heart Foundation, Diabetes UK, the Global Challenges Research Fund, the Government Department for Business, Energy and Industrial Strategy and the Wellcome Trust. The views expressed are those of the author(s) and not necessarily those of the Wellcome Trust, the NHS, the NIHR or the Department of Health.
Funder: The Section of Endocrinology and Investigative Medicine is funded by grants from the MRC, NIHR and is supported by the NIHR Biomedical Research Centre Funding Scheme and the NIHR/Imperial Clinical Research Facility. W.S.D. is funded by an NIHR Research Professorship and an NIHR Senior Investigator Award. This work was supported by a Sir Henry Dale Fellowship jointly funded by The Wellcome Trust and The Royal Society to BMO (105545/Z/14/Z). Grants from the Tyrolean Science Fund to JMRP agreement F.18896. KR and GSHY are supported by the MRC Metabolic Diseases Unit (MC_UU_00014/1). BYHL is supported by a BBSRC Project Grant (BB/S017593/1). JAT is supported by an NIHR Clinical Lectureship (CL-2019-14-504). The Cambridge Brain Bank is supported by the NIHR Cambridge Biomedical Research Centre. SMM was funded by a Commonwealth Scholarship and WHC by the Ford Physiology Fund Endowment. AM and I-MA are supported by MRC intramural funding and ERC Advanced Grant (787470-IntraGutSex).
Keywords
Journal Title
Conference Name
Journal ISSN
2041-1723
Volume Title
Publisher
Publisher DOI
Sponsorship
MRC (MC_UU_00014/1)