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All-trans retinoic acid promotes neural lineage entry by pluripotent embryonic stem cells via multiple pathways

Jianfeng Lu12, Li Tan12, Ping Li12, Hui Gao3, Bo Fang12, Shoudong Ye12, Zhe Geng12, Ping Zheng3 and Houyan Song12*

Author Affiliations

1 Department of Molecular Genetics, Shanghai Medical School, Fudan University, Shanghai, PR China

2 Key Laboratory of Molecular Medicine, Ministry of Education, PR China

3 State Key Laboratory of Medical Neurobiology, PR China

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BMC Cell Biology 2009, 10:57  doi:10.1186/1471-2121-10-57

Published: 30 July 2009



All-trans retinoic acid (RA) is one of the most important morphogens with pleiotropic actions. Its embryonic distribution correlates with neural differentiation in the developing central nervous system. To explore the precise effects of RA on neural differentiation of mouse embryonic stem cells (ESCs), we detected expression of RA nuclear receptors and RA-metabolizing enzymes in mouse ESCs and investigated the roles of RA in adherent monolayer culture.


Upon addition of RA, cell differentiation was directed rapidly and exclusively into the neural lineage. Conversely, pharmacological interference with RA signaling suppressed this neural differentiation. Inhibition of fibroblast growth factor (FGF) signaling did not suppress significantly neural differentiation in RA-treated cultures. Pharmacological interference with extracellular signal-regulated kinase (ERK) pathway or activation of Wnt pathway effectively blocked the RA-promoted neural specification. ERK phosphorylation was enhanced in RA-treated cultures at the early stage of differentiation.


RA can promote neural lineage entry by ESCs in adherent monolayer culture systems. This effect depends on RA signaling and its crosstalk with the ERK and Wnt pathways.