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<p>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 <i>BMAL1</i>, 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.</p>

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Distinct radial glia subtypes regulate midbrain dopaminergic neuron development

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月16日

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  • Emilía Sif Ásgrímsdóttir,
  • Luca Fusar Bassini,
  • Ting Sun,
  • Clàudia Puigsasllosas Pastor,
  • Pia Rivetti di Val Cervo,
  • Daniel Gyllborg,
  • Kawai Lee,
  • Christopher L. Grigsby,
  • Baptiste Jude,
  • Carmen Abaurre,
  • Saiful Islam,
  • Peter Lönnerberg,
  • Carlos Villaescusa,
  • Carmen Saltó,
  • Roger A. Barker,
  • Sten Linnarsson,
  • Goncalo Castelo-Branco,
  • Gioele La Manno,
  • Enrique M. Toledo,
  • Ernest Arenas

摘要

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.