2. Academic Validation
  3. miR-199a functions downstream of MeCP2 in neurons of MECP2 duplication syndrome models

miR-199a functions downstream of MeCP2 in neurons of MECP2 duplication syndrome models

  • iScience. 2025 Oct 16;28(11):113789. doi: 10.1016/j.isci.2025.113789.
Yuichi Akaba 1 2 3,  Satoru Takahashi 1,  Shota Adachi 4,  Masatoshi Nishimura 4,  Keiichiro Suzuki 5 6 7,  Hideyuki Nakashima 8,  Kinichi Nakashima 8,  Ryutaro Kira 9,  Pin Fee Chong 9,  Yasunari Sakai 10,  Yohei Hayashi 11,  Itaru Kushima 12 13,  Daisuke Mori 14 15,  Yuko Arioka 15 16 2,  Hiroki Okumura 15 17,  Atsuo Nakayama 18 19,  Seiji Mizuno 20,  Toshiyuki Yamamoto 21 22,  Fumitaka Osakada 4 23 24,  Norio Ozaki 15,  Keita Tsujimura 2 3 25
Affiliations

Affiliations

  • 1 Department of Pediatrics, Asahikawa Medical University, Asahikawa, Japan.
  • 2 Research Unit for Developmental Disorders, Institute for Advanced Research, Nagoya University, Nagoya, Japan.
  • 3 Group of Brain Function and Development, Nagoya University Neuroscience Institute of the Graduate School of Science, Nagoya, Japan.
  • 4 Laboratory of Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya, Japan.
  • 5 Institute for Advanced Co-Creation Studies, The University of Osaka, Toyonaka, Japan.
  • 6 Graduate School of Engineering Science, The University of Osaka, Toyonaka, Japan.
  • 7 Graduate School of Frontier Bioscience, The University of Osaka, Suita, Japan.
  • 8 Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
  • 9 Department of Pediatric Neurology, Fukuoka Children's Hospital, Fukuoka, Japan.
  • 10 Department of Pediatrics, Kyushu University, Fukuoka, Japan.
  • 11 Research and Development Center, CiRA Foundation, Osaka, Japan.
  • 12 Medical Genomics Center, Nagoya University Hospital, Nagoya, Japan.
  • 13 Department of Psychiatry, Graduate School of Medicine, Nagoya University, Nagoya, Japan.
  • 14 Brain and Mind Research Center, Nagoya University, Nagoya, Japan.
  • 15 Pathophysiology of Mental Disorders, Graduate School of Medicine, Nagoya University, Nagoya, Japan.
  • 16 Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan.
  • 17 Department of Hospital Pharmacy, Nagoya University Hospital, Nagoya, Japan.
  • 18 Department of Cellular Pathology, Institute for Developmental Research, Aichi Developmental Disability Center, Kasugai, Japan.
  • 19 Department of Neurochemistry, Graduate School of Medicine, Nagoya University, Nagoya, Japan.
  • 20 Department of Pediatrics, Central Hospital, Aichi Developmental Disability Center, Kasugai, Japan.
  • 21 Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan.
  • 22 Division of Gene Medicine, Graduate School of Medicine, Tokyo Women's Medical University, Tokyo, Japan.
  • 23 Laboratory of Neural Information Processing, Institute for Advanced Research, Nagoya University, Nagoya, Japan.
  • 24 PRESTO/CREST, Japan Science and Technology Agency, Saitama, Japan.
  • 25 Rett Syndrome Organization Japan, Hirakata, Japan.
PMID: 41244585 DOI: 10.1016/j.isci.2025.113789
Abstract

Duplication of the methyl-CpG-binding protein 2 (MECP2) gene causes MECP2 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 miR-199a-2 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.

Keywords

Biological sciences; Natural sciences; Neuroscience.

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