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First published online May 24, 2006
doi: 10.1242/10.1242/jcs.02955

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Differential actions of the proneural genes encoding Mash1 and neurogenins in Nurr1-induced dopamine neuron differentiation

Chang-Hwan Park^1,2,*, Jin Sun Kang^1,2,*, Jae-Sang Kim³, Seungsoo Chung⁴, Jin-Young Koh⁴, Eun-Hye Yoon^1,2, A. Young Jo^2,5, Mi-Yoon Chang^2,5, Hyun-Chul Koh^2,6, SeJin Hwang⁷, Haeyoung Suh-Kim⁸, Yong-Sung Lee^2,5, Kwang-Soo Kim⁹ and Sang-Hun Lee^2,5,

¹ Department of Microbiology, Hanyang University, Seoul 133-791, Korea
² Institute of Mental Health, Hanyang University, Seoul 133-791, Korea
³ Division of Molecular Life Sciences, Ewha Womans University, Seoul, 120-750, Korea
⁴ Department of Physiology, College of Medicine, Yonsei University, Seoul 120-752, Korea
⁵ Department of Biochemistry and Molecular Biology, Hanyang University, Seoul 133-791, Korea
⁶ Department of Pharmacology, Hanyang University, Seoul 133-791, Korea
⁷ Department of Anatomy and Cell Biology, College of Medicine, Hanyang University, Seoul 133-791, Korea
⁸ Department of Anatomy and Brain Disease Research Center, College of Medicine, Ajou University, Suwon 442-749, Korea
⁹ Molecular Neurobiology Laboratory; McLean Hospital/Harvard Medical School, Belmont, MA, 02478, USA

Author for correspondence (e-mail: leesh{at}hanyang.ac.kr)

Accepted 23 February 2006

The steroid receptor-type transcription factor Nurr1 has a crucial role in the development of the mesencephalic dopamine (DA) neurons. Although ectopic expression of Nurr1 in cultured neural precursor cells is sufficient in establishing the DA phenotype, Nurr1-induced DA cells are morphologically and functionally immature, suggesting the necessity of additional factor(s) for full neuronal differentiation. In this study, we demonstrate that neurogenic basic helix-loop-helix (bHLH) factors Mash1, neurogenins (Ngns) and NeuroD play contrasting roles in Nurr1-induced DA neuronal differentiation. Mash1, but not Ngn2, spatially and temporally colocalized with aldehyde dehydrogenase 2 (AHD2), a specific midbrain DA neuronal progenitor marker, in the early embryonic ventral mesencephalon. Forced expression of Mash1 caused immature Nurr1-induced DA cells to differentiate into mature and functional DA neurons as judged by electrophysiological characteristics, release of DA, and expression of presynaptic DA neuronal markers. By contrast, atonal-related bHLHs, represented by Ngn1, Ngn2 and NeuroD, repressed Nurr1-induced expression of DA neuronal markers. Domain-swapping experiments with Mash1 and NeuroD indicated that the helix-loop-helix domain, responsible for mediating dimerization of bHLH transcription factors, imparts the distinct effect. Finally, transient co-transfection of the atonal-related bHLHs with Nurr1 resulted in an E-box-independent repression of Nurr1-induced transcriptional activation of a reporter containing Nurr1-binding element (NL3) as well as a reporter driven by the native tyrosine hydroxylase gene promoter. Taken together, these findings suggest that Mash1 contributes to the generation of DA neurons in cooperation with Nurr1 in the developing midbrain whereas atonal-related bHLH genes inhibit the process.

Key words: Nurr1, bHLH, Mash1, Neurogenin, Tyrosine hydroxylase (TH), Midbrain dopamine neuron differentiation

This article has been cited by other articles:

				J.-W. Shim, C.-H. Park, Y.-C. Bae, J.-Y. Bae, S. Chung, M.-Y. Chang, H.-C. Koh, H.-S. Lee, S.-J. Hwang, K.-H. Lee, et al. Generation of Functional Dopamine Neurons from Neural Precursor Cells Isolated from the Subventricular Zone and White Matter of the Adult Rat Brain Using Nurr1 Overexpression Stem Cells, May 1, 2007; 25(5): 1252 - 1262. [Abstract] [Full Text] [PDF]

				C.-H. Park, J. S. Kang, Y. H. Shin, M.-Y. Chang, S. Chung, H.-C. Koh, M. H. Zhu, S. B. Oh, Y.-S. Lee, G. Panagiotakos, et al. Acquisition of in vitro and in vivo functionality of Nurr1-induced dopamine neurons FASEB J, December 1, 2006; 20(14): 2553 - 2555. [Abstract] [Full Text] [PDF]