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First published online 1 August 2007
doi: 10.1242/dev.02879

Development 134, 3213-3225 (2007)
Published by The Company of Biologists 2007
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Differences in neurogenic potential in floor plate cells along an anteroposterior location: midbrain dopaminergic neurons originate from mesencephalic floor plate cells

Yuichi Ono1,{dagger},*, Tomoya Nakatani1,{dagger}, Yoshimasa Sakamoto1,{dagger}, Eri Mizuhara1, Yasuko Minaki1, Minoru Kumai1, Akiko Hamaguchi1, Miyuki Nishimura1, Yoko Inoue1, Hideki Hayashi2,{ddagger}, Jun Takahashi2,{ddagger} and Toshio Imai1

1 KAN Research Institute Inc., KobeMI R&D Center 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
2 Department of Neurosurgery, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.

* Author for correspondence (e-mail: y-ono{at}kan.eisai.co.jp)

Accepted 7 June 2007

Directed differentiation and purification of mesencephalic dopaminergic (mesDA) neurons from stem cells are crucial issues for realizing safe and efficient cell transplantation therapies for Parkinson's disease. Although recent studies have identified the factors that regulate mesDA neuron development, the mechanisms underlying mesDA neuron specification are not fully understood. Recently, it has been suggested that mesencephalic floor plate (FP) cells acquire neural progenitor characteristics to generate mesDA neurons. Here, we directly examined this in a fate mapping experiment using fluorescence-activated cell sorting (FACS) with an FP cell-specific surface marker, and demonstrate that mesencephalic FP cells have neurogenic activity and generate mesDA neurons in vitro. By contrast, sorted caudal FP cells have no neurogenic potential, as previously thought. Analysis of dreher mutant mice carrying a mutation in the Lmx1a locus and transgenic mice ectopically expressing Otx2 in caudal FP cells demonstrated that Otx2 determines anterior identity that confers neurogenic activity to FP cells and specifies a mesDA fate, at least in part through the induction of Lmx1a. We further show that FACS can isolate mesDA progenitors, a suitable transplantation material, from embryonic stem cell-derived neural cells. Our data provide insights into the mechanisms of specification and generation of mesDA neurons, and illustrate a useful cell replacement approach for Parkinson's disease.

Key words: Parkinson's disease, Cell replacement therapy, Dopaminergic neuron, Floor plate cells, Neurogenic activity, Lmx1a, Otx2, Embryonic stem cells, Mouse, Rat


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