Open AccessVitamin C Facilitates Dopamine Neuron Differentiation in Fetal Midbrain Through TET 1‐ and JMJD 3‐Dependent Epigenetic Control Manner
Author(s) -
He XiBiao,
Kim Mirang,
Kim SeonYoung,
Yi SangHoon,
Rhee YongHee,
Kim Taeho,
Lee EunHye,
Park ChangHwan,
Dixit Shilpy,
Harrison Fiona E.,
Lee SangHun
Publication year - 2015
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.1932
Subject(s) - biology , neural stem cell , cellular differentiation , dopamine transporter , gene knockdown , neuron , microbiology and biotechnology , midbrain , epigenetics , progenitor cell , dopamine , neurogenesis , stem cell , gene , genetics , endocrinology , dopaminergic , neuroscience , central nervous system
Abstract Intracellular Vitamin C (VC) is maintained at high levels in the developing brain by the activity of sodium‐dependent VC transporter 2 (Svct2), suggesting specific VC functions in brain development. A role of VC as a cofactor for Fe(II)‐2‐oxoglutarate‐dependent dioxygenases has recently been suggested. We show that VC supplementation in neural stem cell cultures derived from embryonic midbrains greatly enhanced differentiation toward midbrain‐type dopamine (mDA) neurons, the neuronal subtype associated with Parkinson's disease. VC induced gain of 5‐hydroxymethylcytosine (5hmC) and loss of H3K27m3 in DA phenotype gene promoters, which are catalyzed by Tet1 and Jmjd3, respectively. Consequently, VC enhanced DA phenotype gene transcriptions in the progenitors by Nurr1, a transcription factor critical for mDA neuron development, to be more accessible to the gene promoters. Further mechanism studies including Tet1 and Jmjd3 knockdown/inhibition experiments revealed that both the 5hmC and H3K27m3 changes, specifically in the progenitor cells, are indispensible for the VC‐mediated mDA neuron differentiation. We finally show that in Svct2 knockout mouse embryos, mDA neuron formation in the developing midbrain decreased along with the 5hmC/H3k27m3 changes. These findings together indicate an epigenetic role of VC in midbrain DA neuron development. S tem C ells 2015;33:1320–1332