β-Arrestin 2 and Epac2 Cooperatively Mediate DRD1-Stimulated Proliferation of Human Neural Stem Cells and Growth of Human Cerebral Organoids

Author:

Dong Xiaoxu12,Chen Yujie3,Lu Juan2,Huang Shichao2,Pei Gang1245ORCID

Affiliation:

1. School of Life Science and Technology, Shanghai Tech University , Shanghai , People’s Republic of China

2. State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell, Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences , Shanghai , People’s Republic of China

3. Uli Schwarz Quantitative Biology Core Facility, Bio-Med Big Data Center, CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences , Shanghai , People’s Republic of China

4. Shanghai Key Laboratory of Signaling and Disease Research, Collaborative Innovation, Center for Brain Science, School of Life Sciences and Technology, Tongji University , Shanghai , People’s Republic of China

5. Institute for Stem Cell and Regeneration, Chinese Academy of Sciences , Beijing , People’s Republic of China

Abstract

Abstract G-protein-coupled receptors (GPCRs) reportedly relay specific signals, such as dopamine and serotonin, to regulate neurogenic processes although the underlying signaling pathways are not fully elucidated. Based on our previous work, which demonstrated dopamine receptor D1 (DRD1) effectively induces the proliferation of human neural stem cells, here we continued to show the knockout of β-arrestin 2 by CRISPR/Cas9 technology significantly weakened the DRD1-induced proliferation and neurosphere growth. Furthermore, inhibition of the downstream p38 MAPK by its specific inhibitors or small hairpin RNA mimicked the weakening effect of β-arrestin 2 knockout. In addition, blocking of Epac2, a PKA independent signal pathway, by its specific inhibitors or small hairpin RNA also significantly reduced DRD1-induced effects. Simultaneous inhibition of β-arrestin 2/p38 MAPK and Epac2 pathways nearly abolished the DRD1-stimulated neurogenesis, indicating the cooperative contribution of both pathways. Consistently, the expansion and folding of human cerebral organoids as stimulated by DRD1 were also mediated cooperatively by both β-arrestin 2/p38 MAPK and Epac2 pathways. Taken together, our results reveal that GPCRs apply at least 2 different signal pathways to regulate neurogenic processes in a delicate and balanced manners.

Funder

National Key Research and Development Program of China

Chinese Academy of Sciences

National Science Foundation

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,Developmental Biology,Molecular Medicine

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