期刊
JOURNAL OF CELL SCIENCE
卷 129, 期 18, 页码 3437-3448出版社
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.192534
关键词
Bradykinin; ERK; Proliferation; Neurogenesis; Ngn2; Cell cycle
类别
资金
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2012/50880-4]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, Brazil (CNPq) [467465/2014-2]
- California Institute for Regenerative Medicine (CIRM) [TR4-06747, DISC-08825]
- National Institutes of Health through the NIH Director's New Innovator Award Program [1-DP2-OD006495-01, R01MH103134, R01MH094753, R21MH107771]
- NARSAD Independent Investigator Grant
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [12/50880-4] Funding Source: FAPESP
During brain development, cells proliferate, migrate and differentiate in highly accurate patterns. In this context, published results indicate that bradykinin functions in neural fate determination, favoring neurogenesis and migration. However, mechanisms underlying bradykinin function are yet to be explored. Our findings indicate a previously unidentified role for bradykinin action in inducing neuron-generating division in vitro and in vivo, given that bradykinin lengthened the G(1)-phase of the neural progenitor cells (NPC) cycle and increased TIS21 (also known as PC3 and BTG2) expression in hippocampus from newborn mice. This role, triggered by activation of the kinin-B2 receptor, was conditioned by ERK1/2 activation. Moreover, immunohistochemistry analysis of hippocampal dentate gyrus showed that the percentage of Ki67(+) cells markedly increased in bradykinin-treated mice, and ERK1/2 inhibition affected this neurogenic response. The progress of neurogenesis depended on sustained ERK phosphorylation and resulted in ERK1/2 translocation to the nucleus in NPCs and PC12 cells, changing expression of genes such as Hes1 and Ngn2 (also known as Neurog2). In agreement with the function of ERK in integrating signaling pathways, effects of bradykinin in stimulating neurogenesis were reversed following removal of protein kinase C (PKC)-mediated sustained phosphorylation.
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