MeCP2 Governs maternal hyperandrogenism-induced cortical defects and behavioral alterations via noncanonical AR-dependent regulation of Mef2c

  • Nat Commun. 2026 May 13;17(1):4225. doi: 10.1038/s41467-026-72942-3.
Yu-Meng Wang  #  1  2 ,  Yanyan Jia  #  3 ,  Yu Wu  #  4 ,  Qiaohang Zhao  5 ,  Yumeng Guo  6 ,  Li Zhang  7 ,  Min Jin  8 ,  Yufang Zheng  9
Affiliations
  • 1. Department of Cardiology, Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 2. Obstetrics and Gynecology Hospital, The institute of Obstetrics and Gynecology, Shanghai key lab of reproduction and development, Shanghai key lab of female reproductive endocrine related diseases, Fudan University, Shanghai, China. [email protected].
  • 3. ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China.
  • 4. Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China.
  • 5. Department of Reproductive Medicine, the Second Affiliated Hospital, Medical School, Zhejiang University, Hangzhou, Zhejiang, China.
  • 6. Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, China.
  • 7. Department of Cardiology, Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 8. Department of Reproductive Medicine, the Second Affiliated Hospital, Medical School, Zhejiang University, Hangzhou, Zhejiang, China. [email protected].
  • 9. Obstetrics and Gynecology Hospital, The institute of Obstetrics and Gynecology, Shanghai key lab of reproduction and development, Shanghai key lab of female reproductive endocrine related diseases, Fudan University, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 42129177 DOI: 10.1038/s41467-026-72942-3
Abstract

Elevated prenatal androgen levels have been associated with an increased incidence of several neurodevelopmental conditions in offspring. However, the underlying mechanisms remain poorly understood. Here we showed that elevated prenatal androgens, modeled via aromatase inhibition in mice, disrupt cortical development and behavior in male offspring by activating androgen receptors (AR). AR interacts with MeCP2 to upregulate the transcription factor MEF2C, bypassing standard androgen response elements. Knocking down Mecp2 or Mef2c, or blocking AR, reversed these effects. Mecp2 duplication alone also upregulated MEF2C, driving similar neurogenesis and behavioral changes that were reversed by AR blockade. This reveals a MeCP2-mediated, non-canonical pathway by which androgens may contribute to male-biased neurodevelopmental conditions.

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