Targeting nuclear receptor corepressors for reversible male contraception

• 成果类型: Article
• 署名作者: Hong, Suk - Hyun; Castro, Glenda; Wang, Dan; Nofsinger, Russell; Kane, Maureen; Folias, Alexandra; Atkins, Annette R.; Yu, Ruth T.; Napoli, Joseph L.; Sassone-Corsi, Paolo; de Rooij, Dirk G.; Liddle, Christopher; Downes, Michael; Evans, Ronald M.
• 署名单位: Salk Institute; University of California System; University of California Berkeley; University of California System; University of California Irvine; Institut National de la Sante et de la Recherche Medicale (Inserm); Utrecht University; University of Sydney; Westmead Institute for Medical Research; University of Sydney; Bristol-Myers Squibb
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8887
• DOI: 10.1073/pnas.2320129121
• 发表日期: 2024-02-27
• 关键词: retinoic acid; spermatogonia differentiation; in-vivo; spermatogenesis; inhibition; testis; metabolism; expression; rats

摘要

Despite numerous female contraceptive options, nearly half of all pregnancies are unintended. Family planning choices for men are currently limited to unreliable condoms and invasive vasectomies with questionable reversibility. Here, we report the development of an oral contraceptive approach based on transcriptional disruption of cyclical gene expression patterns during spermatogenesis. Spermatogenesis involves a continuous series of self- renewal and differentiation programs of spermatogonial stem cells (SSCs) that is regulated by retinoic acid (RA)-dependent activation of receptors (RARs), which control target gene expression through association with corepressor proteins. We have found that the interaction between RAR and the corepressor silencing mediator of retinoid and thyroid hormone receptors (SMRT) is essential for spermatogenesis. In a genetically engineered mouse model that negates SMRT-RAR binding (SMRTmRID mice), the synchronized, cyclic expression of RAR- dependent genes along the seminiferous tubules is disrupted. Notably, the presence of an RA- resistant SSC population that survives RAR de- repression suggests that the infertility attributed to the loss of SMRT- mediated repression is reversible. Supporting this notion, we show that inhibiting the action of the SMRT complex with chronic, low - dose oral administration of a histone deacetylase inhibitor reversibly blocks spermatogenesis and fertility without affecting libido. This demonstration validates pharmacologic targeting of the SMRT repressor complex for non- hormonal male contraception.