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

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

doi:10.3390/ijms23136961

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

^1,2

^1,†

^1,‡,

³,

⁴,

¹,

³,

^1,5,6

^1,2,*

and

Gian Carlo Bellenchi

^1,7,*

Institute of Genetics and Biophysics “A. Buzzati-Traverso”, National Research Council (C.N.R.), 80131 Naples, Italy

Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy

The Ludwig Institute, Department of Cell and Molecular Biology, Karolinska Institute, 17177 Stockholm, Sweden

⁴

Department of Medical-Surgical Sciences and Biotechnologies, University of Rome Sapienza, 040100 Latina, Italy

⁵

Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy

⁶

Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands

⁷

IRCCS Fondazione Santa Lucia, 00179 Rome, Italy

Authors to whom correspondence should be addressed.

^†

Present Address: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

^‡

Present Address: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Academic Editor: Pierre-Olivier Fernagut

Int. J. Mol. Sci. 2022, 23(13), 6961; https://doi.org/10.3390/ijms23136961

Received: 21 May 2022 / Revised: 15 June 2022 / Accepted: 21 June 2022 / Published: 23 June 2022

(This article belongs to the Special Issue Advance in Research on Neurogenesis)

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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. View Full-Text

Keywords: microRNA; dopamine; Nurr1; Lmx1a

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Pulcrano, S.; De Gregorio, R.; De Sanctis, C.; Lahti, L.; Perrone-Capano, C.; Ponti, D.; di Porzio, U.; Perlmann, T.; Caiazzo, M.; Volpicelli, F.; Bellenchi, G.C. Lmx1a-Dependent Activation of miR-204/211 Controls the Timing of Nurr1-Mediated Dopaminergic Differentiation. Int. J. Mol. Sci. 2022, 23, 6961. https://doi.org/10.3390/ijms23136961

AMA Style

Pulcrano S, De Gregorio R, De Sanctis C, Lahti L, Perrone-Capano C, Ponti D, di Porzio U, Perlmann T, Caiazzo M, Volpicelli F, Bellenchi GC. Lmx1a-Dependent Activation of miR-204/211 Controls the Timing of Nurr1-Mediated Dopaminergic Differentiation. International Journal of Molecular Sciences. 2022; 23(13):6961. https://doi.org/10.3390/ijms23136961

Chicago/Turabian Style

Pulcrano, Salvatore, Roberto De Gregorio, Claudia De Sanctis, Laura Lahti, Carla Perrone-Capano, Donatella Ponti, Umberto di Porzio, Thomas Perlmann, Massimiliano Caiazzo, Floriana Volpicelli, and Gian C. Bellenchi. 2022. "Lmx1a-Dependent Activation of miR-204/211 Controls the Timing of Nurr1-Mediated Dopaminergic Differentiation" International Journal of Molecular Sciences 23, no. 13: 6961. https://doi.org/10.3390/ijms23136961

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

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