Regulation of NTRK2 alternative splicing by PRPF40B controls neural differentiation and synaptic plasticity
BDNF signaling through its receptor TRKB plays a critical role in brain development, neuroplasticity, and homeostasis. Alternative splicing of the TRKB gene, NTRK2, generates either the full-length receptor (TRKB-FL) or a truncated isoform (TRKB-T1) that inhibits BDNF signaling and has been implicated in neurodegenerative diseases, psychiatric disorders, and cognitive impairments. Here, we show that PRPF40B, a splicing factor associated with neuronal dysfunction, promotes the production of the TRKB-FL isoform during neuronal differentiation. Silencing PRPF40B increases TRKB-T1 expression and impairs the expression of genes important for neuronal differentiation and synaptic plasticity, both in vitro and in vivo, during early embryogenesis. Our data thus identify PRPF40B as a key regulator of the balance between TRKB receptor isoforms, crucial for fine-tuning neuronal responses and for preventing neuroplasticity or survival impairments, providing also a mechanism for the role of PRPF40B in the pathogenesis of various human neurodegenerative diseases and psychiatric disorders.
Authors
- Younes El Yousfi (ORCID: https://orcid.org/0000-0002-2450-3337)
- Pierre de la Grange (ORCID: https://orcid.org/0000-0001-6361-1878)
- Carlos Suñé (ORCID: https://orcid.org/0000-0002-7991-0458)
- Alonso Rodríguez-Caparrós (ORCID: https://orcid.org/0000-0002-6242-3194)
- Candela Ruiz-Rodríguez (ORCID: https://orcid.org/0000-0002-9421-0839)
- Cristina Hernández-Munaín (ORCID: https://orcid.org/0000-0002-6058-2458)
- Cristina Moreno‐Castro (ORCID: https://orcid.org/0000-0002-7172-7341)
- Jennifer López-Ros (ORCID: https://orcid.org/0000-0003-0559-5309)
- María Duarte-Ruiz (ORCID: https://orcid.org/0000-0001-8284-3893)
- Sandra Jiménez-Lozano (ORCID: https://orcid.org/0000-0002-2909-1343)
- Noelia Martínez-Martínez
- Adela Moreno-Castillo
- Marion Kennel (ORCID: https://orcid.org/0009-0004-7642-7999)
Institutions
- Université Libre de Bruxelles (BE)
- Centro Andaluz de Biología Molecular y Medicina Regenerativa (ES)
- Instituto de Parasitología y Biomedicina "López - Neyra" (ES)
- Universitat de Barcelona (ES)
- Universidad de Sevilla (ES)
- Universidad Pablo de Olavide (ES)
Publication Details
- Journal
- Cell Death and Disease
- Published
- 2025-12-08
- DOI
- https://doi.org/10.1038/s41419-025-08301-9
- Citations
- 1
- Primary Topic
- RNA Research and Splicing
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- Ministerio de Ciencia, Innovación y Universidades
- INFRAFRONTIER
- European Commission
- Horizon 2020 Framework Programme
- European Regional Development Fund