miR-199a functions downstream of MeCP2 in neurons of MECP2 duplication syndrome models
Duplication of the methyl-CpG-binding protein 2 (<i>MECP2</i>) gene causes <i>MECP2</i> duplication syndrome (MDS), a severe neurodevelopmental disorder with an unclear pathology. We previously showed that MeCP2 promotes the processing of specific microRNAs (miRNAs), including miR-199a, to regulate neuronal functions. Here, we demonstrate that neurons derived from MDS model mice and patient-induced pluripotent stem cells (iPSCs) exhibit morphological abnormalities, such as abnormal dendrite outgrowth, enlarged soma size, increased glutamatergic synapse density, and hyperactivation of the mechanistic target of rapamycin (mTOR) signaling. MeCP2 overexpression increased miR-199a production in both models. Blocking miR-199a-5p improved soma size and mTOR activity, while inhibiting miR-199a-3p normalized dendritic outgrowth. Crossing MDS model mice with <i>miR-199a-2</i> knockout mice ameliorated synaptic and mTOR abnormalities. Human MDS cortical organoids exhibited reduced neuronal activity, which was reversed by suppressing miR-199a-5p. These findings identify miR-199a as a key downstream mediator of MeCP2 in MDS, providing new insights into its molecular pathology.
Authors
- Atsuo Nakayama (ORCID: https://orcid.org/0000-0003-1444-0800)
- Hiroki Okumura (ORCID: https://orcid.org/0000-0001-6222-9634)
- Fumitaka Osakada (ORCID: https://orcid.org/0000-0002-9078-1458)
- Keita Tsujimura (ORCID: https://orcid.org/0000-0002-7464-6133)
- Masatoshi Nishimura (ORCID: https://orcid.org/0009-0001-1314-3364)
- Yuichi Akaba (ORCID: https://orcid.org/0000-0001-6226-3648)
- Ryutaro Kira (ORCID: https://orcid.org/0000-0002-6878-5081)
- Satoru Takahashi (ORCID: https://orcid.org/0000-0002-4707-4010)
- Kinichi Nakashima (ORCID: https://orcid.org/0000-0001-5901-9628)
- Yasunari Sakai (ORCID: https://orcid.org/0000-0002-5747-8692)
- Pin Fee Chong (ORCID: https://orcid.org/0000-0002-2046-1360)
- Itaru Kushima
- Hideyuki Nakashima (ORCID: https://orcid.org/0000-0001-9430-5363)
- Yuko Arioka (ORCID: https://orcid.org/0000-0002-1792-8812)
- Yohei Hayashi (ORCID: https://orcid.org/0000-0001-5490-7052)
- Norio Ozaki
- Toshiyuki Yamamoto (ORCID: https://orcid.org/0000-0002-9484-3505)
- S. Adachi (ORCID: https://orcid.org/0000-0002-0400-7555)
- Seiji Mizuno (ORCID: https://orcid.org/0000-0002-1491-4124)
- Keiichiro Suzuki (ORCID: https://orcid.org/0000-0001-5603-9105)
- Daisuke Mori (ORCID: https://orcid.org/0000-0002-5381-6981)
Institutions
- Kyushu University (JP)
- Asahikawa Medical University (JP)
- Toyo University (JP)
- Japan Science and Technology Agency (JP)
- Nagoya University Hospital (JP)
- Fukuoka Children's Hospital and Medical Center for Infectious Diseases (JP)
- Reverse Rett (GB)
- Osaka Prefectural Toyonaka Support School (JP)
- Tokyo Women's Medical University (JP)
- Japan Food Chemical Research Foundation (JP)
- Aichi Developmental Disability Center (JP)
- Nagoya University (JP)
- The University of Osaka (JP)
Publication Details
- Journal
- iScience
- Published
- 2025-10-17
- DOI
- https://doi.org/10.1016/j.isci.2025.113789
- Primary Topic
- Genetics and Neurodevelopmental Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00