Involvement of extracellular vesicle microRNA clusters in developing healthy and Rett syndrome brain organoids

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Rett syndrome (RTT) is a neurodevelopmental disorder caused by de novo mutations in the MECP2 gene. Although miRNAs in extracellular vesicles (EVs) have been suggested to play an essential role in several neurological conditions, no prior study has utilized brain organoids to profile EV-derived miRNAs during normal and RTT-affected neuronal development. Here we report the spatiotemporal expression pattern of EV-derived miRNAs in region-specific forebrain organoids generated from female hiPSCs with a MeCP2:R255X mutation and the corresponding isogenic control. EV miRNA and protein expression profiles were characterized at day 0, day 13, day 40, and day 75. Several members of the hsa-miR-302/367 cluster were identified as having a time-dependent expression profile with RTT-specific alterations at the latest developmental stage. Moreover, the miRNA species of the chromosome 14 miRNA cluster (C14MC) exhibited strong upregulation in RTT forebrain organoids irrespective of their spatiotemporal location. Together, our results suggest essential roles of the C14MC and hsa-miR-302/367 clusters in EVs during normal and RTT-associated neurodevelopment, displaying promising prospects as biomarkers for monitoring RTT progression.
Original languageEnglish
Article number410
Number of pages16
JournalCellular and Molecular Life Sciences
Volume81
Issue number1
DOIs
Publication statusPublished - 1 Dec 2024

Keywords

  • Rett syndrome
  • Brain organoids
  • Extracellular vesicles
  • MicroRNA, chromosome 14 miRNA cluster
  • Hsa-miR-302/367 cluster
  • CELL
  • MECP2
  • MODEL
  • DIFFERENTIATION
  • OVEREXPRESSION
  • TRANSCRIPTION
  • MIGRATION
  • NEURONS
  • DISEASE
  • EXOSOME

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