Abstract
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.
| Original language | English |
|---|---|
| Article number | e2320129121 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 121 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - 20 Feb 2024 |
Bibliographical note
Publisher Copyright:© 2024 the Author(s).
Funding
ACKNOWLEDGMENTS. We thank Yang Dai and Yunqiang Yin for the technical support, Dr. Kistler, Stephen, Dr. Sungtae Kim and Dr. Hye-Won Song for reagents, E. Ong and C. Brondos for administrative support, and all Evans lab members for discussion. R.M.E. holds the March of Dimes Chair in Molecular and Developmental Biology at the Salk Institute and is a Nomis Distinguished Scholar. Research reported in this publication was supported by NIH Grant Nos. CA265762 and CA220468.The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This study was supported by the NGS and Flow Cytometry Salk Cores, which are funded by the Salk Cancer Center (NCI Grant: NIH-NCI CCSG: P30 014195). We thank Yang Dai and Yunqiang Yin for the technical support, Dr. Kistler, Stephen, Dr. Sungtae Kim and Dr. Hye-Won Song for reagents, E. Ong and C. Brondos for administrative support, and all Evans lab members for discussion. R.M.E. holds the March of Dimes Chair in Molecular and Developmental Biology at the Salk Institute and is a Nomis Distinguished Scholar. Research reported in this publication was supported by NIH Grant Nos. CA265762 and CA220468. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This study was supported by the NGS and Flow Cytometry Salk Cores, which are funded by the Salk Cancer Center (NCI Grant: NIH-NCI CCSG: P30 014195).
| Funders | Funder number |
|---|---|
| Memorial Sloan-Kettering Cancer Center | |
| March of Dimes Chair in Molecular and Developmental Biology at the Salk Institute | |
| National Institutes of Health | CA265762, CA220468 |
| National Institutes of Health | |
| National Cancer Institute | P30 014195 |
| National Cancer Institute |
Keywords
- retinoic acid signaling
- spermatogenesis
- transcriptional corepression