Lmx1a-Dependent Activation of miR-204/211 Controls the Timing of Nurr1-Mediated Dopaminergic Differentiation

Salvatore Pulcrano, Roberto De Gregorio, Claudia De Sanctis, Laura Lahti, Carla Perrone-Capano, Donatella Ponti, Umberto Di Porzio, Thomas Perlmann, Massimiliano Caiazzo, Floriana Volpicelli, Gian Carlo Bellenchi

Research output: Contribution to journalArticlepeer-review

Abstract

The development of midbrain dopaminergic (DA) neurons requires a fine temporal and spatial regulation of a very specific gene expression program. Here, we report that during mouse brain development, the microRNA (miR-) 204/211 is present at a high level in a subset of DA precursors expressing the transcription factor Lmx1a, an early determinant for DA-commitment, but not in more mature neurons expressing Th or Pitx3. By combining different in vitro model systems of DA differentiation, we show that the levels of Lmx1a influence the expression of miR-204/211. Using published transcriptomic data, we found a significant enrichment of miR-204/211 target genes in midbrain dopaminergic neurons where Lmx1a was selectively deleted at embryonic stages. We further demonstrated that miR-204/211 controls the timing of the DA differentiation by directly downregulating the expression of Nurr1, a late DA differentiation master gene. Thus, our data indicate the Lmx1a-miR-204/211-Nurr1 axis as a key component in the cascade of events that ultimately lead to mature midbrain dopaminergic neurons differentiation and point to miR-204/211 as the molecular switch regulating the timing of Nurr1 expression.

Original languageEnglish (US)
Article number6961
JournalInternational Journal of Molecular Sciences
Volume23
Issue number13
DOIs
StatePublished - Jul 1 2022

Keywords

  • Lmx1a
  • Nurr1
  • dopamine
  • microRNA

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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