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Acquisition of in vitro and in vivo functionality of Nurr1‐induced dopamine neurons
Author(s) -
Park ChangHwan,
Kang Jin Sun,
Ho Shin Yeon,
Chang MiYoon,
Chung Seungsoo,
Koh HyunChul,
Zhu Mei Hong,
Bae Oh Seog,
Lee YongSung,
Panagiotakos Georgia,
Tabar Vivian,
Studer Lorenz,
Lee SangHun
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.06-6159fje
Subject(s) - forebrain , dopaminergic , biology , neuroscience , striatum , dopamine , sonic hedgehog , embryonic stem cell , midbrain , neural stem cell , neuron , microbiology and biotechnology , tyrosine hydroxylase , transgene , transplantation , in vivo , genetically modified mouse , stem cell , medicine , central nervous system , signal transduction , biochemistry , genetics , gene
Neural precursor cells provide an expandable source of neurons and glia for basic and translational applications. However, little progress has been made in directing naive neural precursors toward specific neuronal fates such as midbrain dopamine (DA) neurons. We have recently demonstrated that transgenic expression of the nuclear orphan receptor Nurr1 is sufficient to drive dopaminergic differentiation of forebrain embryonic rat neural precursors in vitro . However, Nurr1‐induced DA neurons exhibit immature neuronal morphologies and functional properties and are unable to induce behavioral recovery in rodent models of Parkinson's disease (PD). Here, we report on the identification of key genetic factors that drive morphological and functional differentiation of Nurr1‐derived DA neurons. We show that coexpression of Nurr1, Bcl‐XL, and Sonic hedgehog (SHH) or Nurr1 and the proneural bHLH factor Mash1 is sufficient to drive naive rat forebrain precursors into neurons exhibiting the biochemical, electrophysiological, and functional properties of DA neuron in vitro . On transplantation into the striatum of Parkinsonian rats, precursor cells engineered with Nurr1/SHH/Bcl‐XL or Nurr1/Mash1 survived in vivo and differentiated into mature DA neurons that can reverse the behavioral deficits in the grafted animals.—Park, C.‐H., Kang, J. S., Shin, Y. H., Chang, M.‐Y., Chung, S., Koh, H.‐C., Zhu, M. H., Oh, S. B., Lee, Y.‐S., Panagiotakos, G., Tabar, V., Studer, L., and Lee, S.‐H. Acquisition of in vitro and in vivo functionality of Nurr1‐induced dopamine neurons. FASEB J. 20, E1910‐E1923 (2006)