Open AccessGeneration of Dopamine Neurons with Improved Cell Survival and Phenotype Maintenance Using a Degradation‐Resistant Nurr1 Mutant
Author(s) -
Jo AYoung,
Kim MiYoung,
Lee HyunSeob,
Rhee YongHee,
Lee JeongEun,
Baek KwangHyun,
Park ChangHwan,
Koh HyunChul,
Shin Incheol,
Lee YongSung,
Lee SangHun
Publication year - 2009
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.146
Subject(s) - biology , protein kinase b , microbiology and biotechnology , phosphorylation , transcription factor , pi3k/akt/mtor pathway , dopamine , transplantation , phenotype , cancer research , signal transduction , endocrinology , medicine , biochemistry , gene
Abstract Nurr1 is a transcription factor specific for the development and maintenance of the midbrain dopamine (DA) neurons. Exogenous Nurr1 in neural precursor (NP) cells induces the differentiation of DA neurons in vitro that are capable of reversing motor dysfunctions in a rodent model for Parkinson disease. The promise of this therapeutic approach, however, is unclear due to poor cell survival and phenotype loss of DA cells after transplantation. We herein demonstrate that Nurr1 proteins undergo ubiquitin‐proteasome‐system‐mediated degradation in differentiating NP cells. The degradation process is activated by a direct Akt‐mediated phosphorylation of Nurr1 proteins and can be prevented by abolishing the Akt‐target sequence in Nurr1 (Nurr1 Akt ). Overexpression of Nurr1 Akt in NP cells yielded DA neurons in which Nurr1 protein levels were maintained for prolonged periods. The sustained Nurr1 expression endowed the Nurr1 Akt ‐induced DA neurons with resistance to toxic stimuli, enhanced survival, and sustained DA phenotypes in vitro and in vivo after transplantation. STEM CELLS 2009;27:2238–2246