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The intricate balance of neural stem cell (NSC) amplification and neurogenesis is central to nervous system development. Dopamine D1 receptor (DRD1) is a typical G protein-coupled receptor (GPCR) mainly expressed in neurogenic area, with high constitutive activity. The receptor appears in the embryonic period before the formation of mature synaptic contacts, which indicates that dopamine receptor and its constitutive activity play crucial roles in the embryonic brain development. Here, we found that DRD1 was enriched in human NSCs. Inhibition of the receptor activity by its inverse agonists promoted human NSCs proliferation and impeded it differentiation. These results were also mimicked by genetic knockdown of DRD1, which also blocked the effects of inverse agonists, suggesting a receptor-dependent manner. More interestingly, knock-in A229T mutant with reduced DRD1 constitutive activity by CRISPR-Cas9 genome editing technology resulted into increased endogenous human NSCs proliferation. These results were well reproduced in human cerebral organoids and inhibition of the DRD1 constitutive activity by its inverse agonists induced the expansion and folding of human cerebral organoids. The anatomic analysis uncovered that decreasing the constitutive activity of DRD1 by its inverse agonists promoted the NSCs proliferation and maintenance that led to hindered cortical neurogenesis. Further mechanistic studies revealed that the PKC-CBP pathway was involved in the regulation by DRD1. Thus, our findings indicate that the constitutive activity of DRD1 and possibly other GPCRs plays an important role in the development of human nervous system. © AlphaMed Press 2020 SIGNIFICANCE
In the current study, the authors first demonstrated a potential role of DRD1 constitutive activity for the regulation of neurogenesis in human brain development. Inhibiting the constitutive activity of the DRD1 promoted human NSC amplification and thus induced expansion and folding of human cerebral organoids, thereby impeded the process of neurogenesis. The DRD1 mediates its action on NSCs partially through down-regulating the genesis of neurons in a CBP/p300-dependent fashion by reducing the level of PKC phosphorylation. This study also provides another insight that there might be strategies to effectively control the time of neural precursor (NP) amplification or neuron transition by flexibly and precisely regulating the constitutive activity of DRD1 and modulating the multiple stages of adult NSC development in a single therapeutic strategy is possible to fight against age-related decline in hippocampal NSC.
This article was published in the following journal.
Name: Stem cells (Dayton, Ohio)
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A receptor activity-modifying protein that is a subunit of specific G-PROTEIN COUPLED RECEPTORS. The CALCITONIN GENE-RELATED PEPTIDE RECEPTOR is formed from a dimer of this protein and CALCITONIN RECEPTOR-LIKE PROTEIN, while an isoform of the ISLET AMYLOID POLYPEPTIDE RECEPTOR is formed from this protein dimerizing with the CALCITONIN RECEPTOR.
A ubiquitously expressed G-protein-coupled receptor kinase subtype that has specificity for the agonist-occupied form of BETA-ADRENERGIC RECEPTORS and a variety of other G-PROTEIN-COUPLED RECEPTORS. Although it is highly homologous to G-PROTEIN-COUPLED RECEPTOR KINASE 2, it is not considered to play an essential role in regulating myocardial contractile response.
A family of serine-threonine kinases that are specific for G-PROTEIN-COUPLED RECEPTORS. They are regulatory proteins that play a role in G-protein-coupled receptor densensitization.
G-protein-coupled cell surface receptors for ADRENOMEDULLIN. They are formed by the heterodimerization of CALCITONIN RECEPTOR-LIKE PROTEIN and either RECEPTOR ACTIVITY-MODIFYING PROTEIN 2 or RECEPTOR ACTIVITY-MODIFYING PROTEIN 3.
G-protein coupled receptors that are formed through the dimerization of the CALCITONIN RECEPTOR with a RECEPTOR ACTIVITY-MODIFYING PROTEIN. Their affinity for ISLET AMYLOID POLYPEPTIDE is dependent upon which of several receptor activity-modifying protein subtypes they are bound to.
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