Mash1 and neurogenin 2 enhance survival and differentiation of neural precursor cells after transplantation to rat brains via distinct modes of action.

Abstract	Neural precursor cells (NPCs) are regarded as a promising source of donor cells in transplantation-based therapies for neurodegenerative disorders. However, poor survival and limited neuronal differentiation of the transplanted NPCs remain critical limitations for developing therapeutic strategies. In this study, we investigated the effects of the proneural basic helix-loop-helix (bHLH) transcription factors Mash1 and Neurogenin 2 (Ngn2) in neuronal differentiation and survival of NPCs. Induction of Mash1 or Ngn2 expression strikingly enhanced neuronal differentiation of cultured NPCs in vitro. Ngn2-transduced NPCs underwent a rapid cell cycle arrest, which often accompanies differentiation. In contrast, cells continuously expanded upon Mash1 expression during NPC differentiation. Notably, sonic hedgehog (SHH) was upregulated by Mash1 and mediated the proliferative and survival effects of Mash1 on NPCs. Upon transplantation into adult rat brains, Mash1-expressing NPCs yielded large grafts enriched with neurons compared to control LacZ-transduced NPCs. Interestingly, enhancements in neuronal yield, as well as in donor cell survival, were also achieved by transplanting Ngn2-transduced NPCs. We show that a differentiation stage- and cell density-dependent survival effect of Ngn2 involves neurotrophin3 (NT3)/TrkC-mediated signaling. Together, these findings suggest potential benefits of bHLH gene manipulation to develop successful transplantation strategies for brain disorders.
Authors	Sang-Hoon Yi, A-Young Jo, Chang-Hwan Park, Hyun-Chul Koh, Rae-Hee Park, Haeyoung Suh-Kim, Incheol Shin, Yong-Sung Lee, Jaesang Kim, Sang-Hun Lee
Journal	Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 16 Issue 11 Pg. 1873-82 (Nov 2008) ISSN: 1525-0024 [Electronic] United States
PMID	18781144 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Ascl1 protein, rat Basic Helix-Loop-Helix Transcription Factors Hedgehog Proteins Nerve Tissue Proteins Neurog2 protein, rat Neurotrophin 3
Topics	Animals Basic Helix-Loop-Helix Transcription Factors (biosynthesis, genetics) Brain (cytology) Cell Differentiation (physiology) Cell Proliferation Cell Survival (physiology) Cells, Cultured Embryonic Stem Cells (cytology, transplantation) Hedgehog Proteins (physiology) In Vitro Techniques Mice Nerve Tissue Proteins (biosynthesis, genetics) Neurons (cytology, transplantation) Neurotrophin 3 (physiology) Rats Rats, Sprague-Dawley Signal Transduction Transduction, Genetic

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