Distinct radial glia subtypes regulate midbrain dopaminergic neuron development
Understanding the development of midbrain dopaminergic (mesDA) neurons is essential for advancing cell replacement therapies for Parkinson's disease. In the developing ventral midbrain (VM), radial glia (Rgl) cells are the progenitors of mesDA neurons. However, distinct Rgl subtypes have recently been identified, and their individual roles are unclear. Here we analyze transcriptomic data from mouse and human VM Rgl to define their contributions to mesDA neuron development. We identify Rgl1 as the progenitor of the mesDA lineage, and reveal a Rgl1 transcriptional network coordinated by BMAL1, which we validate as a new regulator of mesDA neurogenesis. Moreover, we uncover Rgl3 as a key signaling subtype and show that factors expressed by Rgl3 promote the survival and yield of human stem cell-derived mesDA neurons. Our findings delineate distinct roles of Rgl subtypes, elucidate lineage relationships in the developing VM and uncover new factors that improve the derivation of clinically relevant human mesDA neurons.
Authors
- Enrique M. Toledo (ORCID: https://orcid.org/0000-0002-1460-4708)
- Ernest Arenas (ORCID: https://orcid.org/0000-0003-0197-6577)
- Gonçalo Castelo‐Branco (ORCID: https://orcid.org/0000-0003-2247-9393)
- Daniel Gyllborg (ORCID: https://orcid.org/0000-0002-1429-6426)
- Christopher L. Grigsby
- Ting Sun (ORCID: https://orcid.org/0000-0002-7104-7215)
- Emilía Sif Ásgrímsdóttir (ORCID: https://orcid.org/0000-0003-1509-6853)
- Pia Rivetti di Val Cervo (ORCID: https://orcid.org/0000-0001-5999-1230)
- Peter Lönnerberg (ORCID: https://orcid.org/0009-0009-0965-2906)
- Luca Fusar Bassini (ORCID: https://orcid.org/0009-0005-8256-8074)
- Saiful Islam (ORCID: https://orcid.org/0000-0001-5777-9164)
- Clàudia Puigsasllosas Pastor
- Carmen Abaurre (ORCID: https://orcid.org/0000-0002-7800-2829)
- Carlos Villaescusa
- Carmen Saltó
- Kawai Lee
- Baptiste Jude
- Roger A. Barker
- Gioele La Manno
Institutions
- Queen's University Belfast (GB)
- Stockholm University (SE)
- Novo Nordisk (Denmark) (DK)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- Science for Life Laboratory (SE)
- Karolinska Institutet (SE)
- Novo Nordisk (Finland) (FI)
- Italian Medicines Agency (IT)
- Freenome (United States) (US)
- École Polytechnique Fédérale de Lausanne (CH)
- Universitat de Barcelona (ES)
Publication Details
- Journal
- Nature Neuroscience
- Published
- 2026-02-16
- DOI
- https://doi.org/10.1038/s41593-026-02200-8
- Primary Topic
- Pluripotent Stem Cells Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00