Cell cycle and p53 gate the direct conversion of human fibroblasts to dopaminergic neurons.

Abstract

The direct conversion of fibroblasts to induced dopaminergic (iDA) neurons and other cell types demonstrates the plasticity of cell fate. The low efficiency of these relatively fast conversions suggests that kinetic barriers exist to safeguard cell-type identity. Here we show that suppression of p53, in conjunction with cell cycle arrest at G1 and appropriate extracellular environment, markedly increase the efficiency in the transdifferentiation of human fibroblasts to iDA neurons by Ascl1, Nurr1, Lmx1a and miR124. The conversion is dependent on Tet1, as G1 arrest, p53 knockdown or expression of the reprogramming factors induces Tet1 synergistically. Tet1 knockdown abolishes the transdifferentiation while its overexpression enhances the conversion. The iDA neurons express markers for midbrain DA neurons and have active dopaminergic transmission. Our results suggest that overcoming these kinetic barriers may enable highly efficient epigenetic reprogramming in general and will generate patient-specific midbrain DA neurons for Parkinson's disease research and therapy.

• Authors: Houbo Jiang, Zhimin Xu, Ping Zhong, Yong Ren, Gaoyang Liang, Haley A Schilling, Zihua Hu, Yi Zhang, Xiaomin Wang, Shengdi Chen, Zhen Yan, Jian Feng
• Journal: Nature communications (Nat Commun) Vol. 6 Pg. 10100 (Dec 07 2015) ISSN: 2041-1723 [Electronic] England
• PMID: 26639555 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• ASCL1 protein, human
• Basic Helix-Loop-Helix Transcription Factors
• DNA-Binding Proteins
• LIM-Homeodomain Proteins
• LMX1A protein, human
• MIRN124 microRNA, human
• MicroRNAs
• NR4A2 protein, human
• Nuclear Receptor Subfamily 4, Group A, Member 2
• Proto-Oncogene Proteins
• TP53 protein, human
• Transcription Factors
• Tumor Suppressor Protein p53
• Mixed Function Oxygenases
• TET1 protein, human

Topics

• Basic Helix-Loop-Helix Transcription Factors (genetics, metabolism)
• Cell Cycle
• Cell Cycle Checkpoints
• Cell Line
• Cell Transdifferentiation (genetics)
• Cellular Reprogramming
• DNA-Binding Proteins (genetics, metabolism)
• Dopaminergic Neurons (cytology)
• Fibroblasts (cytology)
• G1 Phase Cell Cycle Checkpoints (genetics)
• Gene Knockdown Techniques
• Humans
• LIM-Homeodomain Proteins (genetics, metabolism)
• Mesencephalon
• MicroRNAs (genetics)
• Mixed Function Oxygenases
• Nuclear Receptor Subfamily 4, Group A, Member 2 (genetics, metabolism)
• Proto-Oncogene Proteins (genetics, metabolism)
• Transcription Factors (genetics, metabolism)
• Tumor Suppressor Protein p53 (genetics)