Nato3 integrates with the Shh-Foxa2 transcriptional network regulating the differentiation of midbrain dopaminergic neurons

Einat Nissim-Eliraz, Sophie Zisman, Omri Schatz, Nissim Ben-Arie*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Mesencephalic dopaminergic (mesDA) neurons originate from the floor plate of the midbrain, a transient embryonic organizing center located at the ventral-most midline. Since the loss of mesDA leads to Parkinson's disease, the molecular mechanisms controlling the genesis and differentiation of dopaminergic progenitors are extensively studied and the identification and characterization of new genes is of interest. Here, we show that the expression of the basic helix-loop-helix transcription factor Nato3 (Ferd3l) increases in parallel to the differentiation of SN4741 dopaminergic cells in vitro. Nato3 transcription is directly regulated by the transcription factor Foxa2, a target and effector of the Sonic hedgehog (Shh) signaling cascade. Moreover, pharmacological inhibition of Shh signaling downregulated the expression of Nato3, thus defining Nato3 as a novel component of one of the major pathways controlling cell patterning and generation of mesDA. Furthermore, we show that Nato3 regulated Shh and Foxa2 through a novel feed-backward loop. Up- and downregulation of Nato3 further affected the transcription of Nurr1, implicated in the genesis of mesDA, but not of TH. Taken together, these data shed new light on the transcriptional networks controlling the generation of mesDA and may be utilized in the efforts to direct stem cells towards a dopaminergic fate.

Original languageAmerican English
Pages (from-to)13-27
Number of pages15
JournalJournal of Molecular Neuroscience
Volume51
Issue number1
DOIs
StatePublished - Sep 2013

Bibliographical note

Funding Information:
Acknowledgments The research was supported by grants from the Israel Science Foundation (431/07) and the Legacy-Heritage Biomedical Program of the Israel Science Foundation (1914/08). We thank Eti Golenser and Theodora Bar-El for carefully reading and correcting the manuscript. We are grateful to Dr. Naomi Melamed-Book for expert assistance with confocal imaging.

Keywords

  • Differentiation
  • Midbrain dopaminergic neuron
  • Nato3
  • SN4741 cell line
  • Transcriptional regulation

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