Interactions between the NO-citrulline cycle and brain-derived neurotrophic factor in differentiation of neural stem cells.
The diffusible messenger NO plays multiple roles in neuroprotection, neurodegeneration, and brain plasticity. Argininosuccinate synthase (AS) is a ubiquitous enzyme in mammals and the key enzyme of the NO-citrulline cycle, because it provides the substrate L-arginine for subsequent NO synthesis by inducible, endothelial, and neuronal NO synthase (NOS). Here, we provide evidence for the participation of AS and of the NO-citrulline cycle in the progress of differentiation of neural stem cells (NSC) into neurons, astrocytes, and oligodendrocytes. AS expression and activity and neuronal NOS expression, as well as l-arginine and NO(x) production, increased along neural differentiation, whereas endothelial NOS expression was augmented in conditions of chronic NOS inhibition during differentiation, indicating that this NOS isoform is amenable to modulation by extracellular cues. AS and NOS inhibition caused a delay in the progress of neural differentiation, as suggested by the decreased percentage of terminally differentiated cells. On the other hand, BDNF reversed the delay of neural differentiation of NSC caused by inhibition of NO(x) production. A likely cause is the lack of NO, which up-regulated p75 neurotrophin receptor expression, a receptor required for BDNF-induced differentiation of NSC. We conclude that the NO-citrulline cycle acts together with BDNF for maintaining the progress of neural differentiation.
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, 05508-900 São Paulo, Brazil.
Claudiana
C
Lameu
Cleber A
CA
Trujillo
Telma T
TT
Schwindt
Priscilla D
PD
Negraes
Micheli M
MM
Pillat
Katia L P
KL
Morais
Ivo
I
Lebrun
Henning
H
Ulrich
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D002956:Citrulline / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D009419:Nerve Tissue Proteins; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D009419:Nerve Tissue Proteins; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor; C068313:Ngfr protein, rat; D002956:Citrulline; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase