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<p>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 <i>Mecp2</i> or <i>Mef2c</i>, or blocking AR, reversed these effects. <i>Mecp2</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月13日

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  • Yu-Meng Wang,
  • Yanyan Jia,
  • Yu Wu,
  • Qiaohang Zhao,
  • Yumeng Guo,
  • Li Zhang,
  • Min Jin,
  • Yufang Zheng

摘要

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.