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Background <p>Rett Syndrome (RTT) is a neurodevelopmental disorder primarily caused by mutations in the <i>MECP2</i> gene. Despite its monogenic nature, the molecular events contributing to RTT pathogenesis are not fully elucidated.</p> Methods <p>We applied a multi-omics approach to comprehensively analyse the spatiotemporal gene and protein expression patterns in MeCP2-mutant (RTT) and isogenic control (IC) forebrain organoids. Dorsal and ventral forebrain organoids were cultured for 75 days using patient-derived RTT and IC hiPSC lines. Transcriptomics and proteomics profiles were characterized at days 0, 13, 40, and 75, corresponding to distinct neurodevelopmental phases.</p> Results <p>The spatiotemporal transcriptomic analysis revealed alterations in GABAergic signaling at the latest neurodevelopmental stages, while changes in neuronal development, DNA-associated processes, and post-transcriptional regulation were found to occur across different stages. These changes were also observed at the protein level and in independent validation datasets. Notably, differentially expressed lncRNA genes such as <i>MIR137HG</i> and <i>PWRN1</i> may act as regulators of these affected processes. Moreover, our results provide systematic evidence for the involvement of imprinted genes in RTT pathology.</p> Conclusions <p>Together, our study lays the foundation for future studies to functionally validate the significance of the identified processes and molecular targets in RTT pathogenesis, and to assess their value as therapeutic targets.</p> Graphical Abstract <p></p>

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Multi-omics characterization of developing forebrain organoids unravels the dynamic molecular events of Rett syndrome pathogenesis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月21日

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  • Jarno Koetsier,
  • Nasim Bahram Sangani,
  • Ana Rita Gomes,
  • Maria Margarida Diogo,
  • Tiago G. Fernandes,
  • Freek G. Bouwman,
  • Edwin C. M. Mariman,
  • Mehrnaz Ghazvini,
  • Leon J. Schurgers,
  • Joost Gribnau,
  • Leopold M.G. Curfs,
  • Chris P. Reutelingsperger,
  • Lars M.T. Eijssen

摘要

Background

Rett Syndrome (RTT) is a neurodevelopmental disorder primarily caused by mutations in the MECP2 gene. Despite its monogenic nature, the molecular events contributing to RTT pathogenesis are not fully elucidated.

Methods

We applied a multi-omics approach to comprehensively analyse the spatiotemporal gene and protein expression patterns in MeCP2-mutant (RTT) and isogenic control (IC) forebrain organoids. Dorsal and ventral forebrain organoids were cultured for 75 days using patient-derived RTT and IC hiPSC lines. Transcriptomics and proteomics profiles were characterized at days 0, 13, 40, and 75, corresponding to distinct neurodevelopmental phases.

Results

The spatiotemporal transcriptomic analysis revealed alterations in GABAergic signaling at the latest neurodevelopmental stages, while changes in neuronal development, DNA-associated processes, and post-transcriptional regulation were found to occur across different stages. These changes were also observed at the protein level and in independent validation datasets. Notably, differentially expressed lncRNA genes such as MIR137HG and PWRN1 may act as regulators of these affected processes. Moreover, our results provide systematic evidence for the involvement of imprinted genes in RTT pathology.

Conclusions

Together, our study lays the foundation for future studies to functionally validate the significance of the identified processes and molecular targets in RTT pathogenesis, and to assess their value as therapeutic targets.

Graphical Abstract