New insights into “GPR40‐CREB interaction inadult neurogenesis” specific for primates

Abstract

Polyunsaturated fatty acids (PUFA), such as docosahexaenoic (DHA) and arachidonic acids (ARA) are known to be closely related to the brain development and also have beneficial effects on adult neurogenesis, learning, and mental disorders. Although PUFA were demonstrated as ligands for G protein-coupled receptor 40 (GPR40), their signaling mechanism in the brain, especially in the neurogenic niche, remains unknown. Using a monkey model of ischemia-enhanced hippocampal neurogenesis, we studied the spatial correlation between GPR40 and the phosphorylated cAMP response element-binding protein (pCREB), a transcription factor involved in adult neurogenesis, learning and memory. Furthermore, the brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinase B (TrkB), both being downstream gene transcripts of pCREB, were studied. Similar to the dynamic change of GPR40 as the authors reported previously, pCREB was up-regulated significantly after transient global brain ischemia on Western blots, and this was associated with an enhanced hippocampal neurogenesis. Immunofluorescence microscopic analysis showed that GPR40 and pCREB expression patterns were completely identical, and they were coexpressed in both mature and newborn neurons as well as in the astrocytes residing in the subgranular zone (SGZ). GPR40/pCREB double-positive cells significantly increased in the SGZ on day 15 after ischemia. The mature form of BDNF (mBDNF) and TrkB receptor showed no remarkable changes on Western blots, although proBDNF (precursor of mBDNF) was maximal on day 9. Immunofluorescence microscopy showed that the newborn neurons expressed BDNF, but not TrkB. These results altogether suggest that PUFA, GPR40, pCREB, and BDNF may be engaged in the same signaling pathway to promote neurogenesis in the adult primate hippocampus.

Role of GPR40 for Fish Oil PUFA-mediated BDNF Synthesis in the Monkey Hippocampus

“…Dissected fresh samples of the hippocampal DG were immediately put into the liquid nitrogen and stored at -80°C until use. Diverse PUFA including DHA are well known endogenous in vitro agonists/ligands for GPR40 receptor [17][18][19]27], which are highly abundant in Fish oil compared to other animal sources. GW1100 is very highly selective antagonist of GPR40 being 1000 time specific for the GPR40 receptor [18,27].…”

“…Recently, Boneva and Yamashima [19] suggested in the ischemic monkey experimental paradigm that PUFA, GPR40, phosphorylated cAMP response element-binding protein (pCREB), and BDNF may be engaged in the same signaling pathway for promoting neurogenesis in the adult hippocampus. They speculated that PUFA initially bind to GPR40 and activate intracellular downstream messengers such as Gαq, PLC, and PKC.…”

“…It was focused because of the two reasons; 1) Since the extent of GPR40 protein expression in the brain was much larger in primates compared to rodents [16,17,[19][20][21][22], the monkey hippocampus was appropriate for studying dynamic changes at the protein level, and 2) it showed a remarkable up-regulation of adult neurogenesis on the 2 nd week after ischemia, being in deep association with BDNF synthesis [19][20][21][22][23]. Since the PUFA-GPR40-CREB-BDNF signaling was already indicated in our ischemic monkey experimental paradigms, the monkey hippocampal tissues before and after the ischemic insult were focused for the present in vitro analysis to compare both.…”

CREB Signaling in Neural Stem/Progenitor Cells: Implications for a Role in Brain Tumors

“…All the above mentioned studies were performed in animal model organisms or NSPCs derived from these. So far there are no reports on the role of the CREB pathway in human NSPCs but recent work shows that CREB is activated and functional in neurogenic cells in the adult primate (Japanese macacque) brain (Boneva & Yamashima 2011).…”

“…To date there has been no evidence linking CREB to brain cancer development or progression in vivo, although a number of recent findings linking CREB activity to PTEN and growth factors, together with the knowledge of CREB's role in NSPC biology, lend support to the view that CREB is an important factor in brain tumour signalling pathways. Of note, recent data shows that CREB is a protein target of PTEN phosphatase activity and that PTEN loss induces CREBdependent gene expression and cell growth (Boneva & Yamashima 2011). PTEN is a tumour suppressor gene frequently mutated in many cancers including the most aggressive forms of brain cancer, glioblastoma multiforme and related astrocytomas.…”