title: Bradykinin promotes neuron-generating division of neural progenitor cells through ERK activation.
abstract: 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 G1-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.
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo 05508-900, Brazil.
authors.forename: Micheli M
authors.identifier: 0000-0002-6753-6083
authors.initials: MM
authors.lastname: Pillat
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo 05508-900, Brazil.
authors.forename: Claudiana
authors.initials: C
authors.lastname: Lameu
authors.affiliation: Departments of Pediatrics and Cellular & Molecular Medicine, University of California San Diego, San Diego, CA 92093-0695, USA.
authors.forename: Cleber A
authors.identifier: 0000-0002-0675-6437
authors.initials: CA
authors.lastname: Trujillo
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo 05508-900, Brazil.
authors.forename: Talita
authors.identifier: 0000-0002-3350-4569
authors.initials: T
authors.lastname: Glaser
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas e da Saúde, UFRGS, Porto Alegre 90035 000, Brazil.
authors.forename: Angélica R
authors.identifier: 0000-0002-8202-609X
authors.initials: AR
authors.lastname: Cappellari
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo 05508-900, Brazil Departments of Pediatrics and Cellular & Molecular Medicine, University of California San Diego, San Diego, CA 92093-0695, USA.
authors.forename: Priscilla D
authors.identifier: 0000-0001-7876-1895
authors.initials: PD
authors.lastname: Negraes
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas e da Saúde, UFRGS, Porto Alegre 90035 000, Brazil.
authors.forename: Ana M O
authors.initials: AM
authors.lastname: Battastini
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo 05508-900, Brazil.
authors.forename: Telma T
authors.identifier: 0000-0001-5603-7425
authors.initials: TT
authors.lastname: Schwindt
authors.affiliation: Departments of Pediatrics and Cellular & Molecular Medicine, University of California San Diego, San Diego, CA 92093-0695, USA.
authors.forename: Alysson R
authors.initials: AR
authors.lastname: Muotri
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo 05508-900, Brazil henning@iq.usp.br.
authors.forename: Henning
authors.identifier: 0000-0002-2114-3815
authors.initials: H
authors.lastname: Ulrich
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016716:PC12 Cells; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D000242:Cyclic AMP; D048049:Extracellular Signal-Regulated MAP Kinases; D001920:Bradykinin; D002118:Calcium
keywords: Bradykinin; Cell cycle; ERK; Neurogenesis; Ngn2; Proliferation