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The Journal of Neuroscience, April 2, 2008, 28(14):3644-3656; doi:10.1523/JNEUROSCI.0311-08.2008

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Development/Plasticity/Repair
Effects on Differentiation of Embryonic Ventral Midbrain Progenitors by Lmx1a, Msx1, Ngn2, and Pitx3

Laurent Roybon, ^* Tord Hjalt, ^* Nicolaj S. Christophersen, Jia-Yi Li, and Patrik Brundin

Neuronal Survival Unit, Department of Experimental Medical Science, 221 84 Lund, Sweden

Correspondence should be addressed to Laurent Roybon, Neuronal Survival Unit, Division for Neuroscience, Department of Experimental Medical Science, Wallenberg Neuroscience Center, BMC A10, 221 84 Lund, Sweden. Email: laurent.roybon{at}med.lu.se

Neurons derived from neural stem cells could potentially be used for cell therapy in neurodegenerative disorders, such as Parkinson's disease. To achieve controlled differentiation of neural stem cells, we expressed transcription factors involved in the development of midbrain dopaminergic neurons in rat and human neural progenitors. Using retroviral-mediated transgene delivery, we overexpressed Lmx1a (LIM homeobox transcription factor 1, alpha), Msx1 (msh homeobox homolog 1), Ngn2 (neurogenin 2), or Pitx3 (paired-like homeodomain transcription factor 3) in neurospheres derived from embryonic day 14.5 rat ventral mesencephalic progenitors. We also expressed either Lmx1a or Msx1 in the human embryonic midbrain-derived progenitor cell line NGC-407. Rat cells transduced with Ngn2 exited the cell cycle and expressed the neuronal marker microtubule-associated protein 2 and catecholamine-neuron protein vesicular monoamine transporter 2. Interestingly, Pitx3 downregulated the expression of SOX2 (SRY-box containing gene 2) and Nestin, altered cell morphology, but never induced neuronal or glial differentiation. Ngn2 exhibited a strong neuron-inducing effect. In contrast, few Lmx1a-transduced cells matured into neurons, and Msx1 overexpression promoted oligodendrogenesis rather than neuronal differentiation. Importantly, none of these four genes, alone or in combination, enhanced differentiation of rat neural stem cells into dopaminergic neurons. Notably, the overexpression of Lmx1a, but not Msx1, in human neural progenitors increased the yield of tyrosine hydroxylase-immunoreactive cells by threefold. Together, we demonstrate that induced overexpression of transcription factor genes has profound and specific effects on the differentiation of rat and human midbrain progenitors, although few dopamine neurons are generated.

Key words: ventral mesencephalic progenitors; cell line; neuronal differentiation; dopaminergic neurons; Ngn2; Pitx3; Msx1; Lmx1a; retrovirus

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Received Dec. 23, 2006; revised Feb. 21, 2008; accepted Feb. 25, 2008.

Correspondence should be addressed to Laurent Roybon, Neuronal Survival Unit, Division for Neuroscience, Department of Experimental Medical Science, Wallenberg Neuroscience Center, BMC A10, 221 84 Lund, Sweden. Email: laurent.roybon{at}med.lu.se

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