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Effects on differentiation of embryonic ventral midbrain progenitors by Lmx1a, MSX1, Ngn2, and Pitx3.

Roybon, Laurent LU ; Hjalt, Tord LU ; Christophersen, Nicolaj LU ; Li, Jia-Yi LU and Brundin, Patrik LU (2008) In The Journal of neuroscience : the official journal of the Society for Neuroscience 28(14). p.3644-3656
Abstract
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... (More)
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. (Less)
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author
organization
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type
Contribution to journal
publication status
published
subject
in
The Journal of neuroscience : the official journal of the Society for Neuroscience
volume
28
issue
14
pages
3644 - 3656
publisher
Society for Neuroscience
external identifiers
  • WOS:000254623500014
  • PMID:18385323
  • Scopus:43649094851
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.0311-08.2008
language
English
LU publication?
yes
id
d7dcb553-4966-4ad2-8298-5db48337b6e3 (old id 1147835)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/18385323?dopt=Abstract
date added to LUP
2008-05-08 09:16:51
date last changed
2017-01-01 07:51:51
@article{d7dcb553-4966-4ad2-8298-5db48337b6e3,
  abstract     = {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.},
  author       = {Roybon, Laurent and Hjalt, Tord and Christophersen, Nicolaj and Li, Jia-Yi and Brundin, Patrik},
  issn         = {1529-2401},
  language     = {eng},
  number       = {14},
  pages        = {3644--3656},
  publisher    = {Society for Neuroscience},
  series       = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
  title        = {Effects on differentiation of embryonic ventral midbrain progenitors by Lmx1a, MSX1, Ngn2, and Pitx3.},
  url          = {http://dx.doi.org/10.1523/JNEUROSCI.0311-08.2008},
  volume       = {28},
  year         = {2008},
}