The role of basic fibroblast growth factor (bFGF) in newborn rat brain.

摘要

While the control of neuron generation by growth factors has been characterized in cell culture, little is known about the potential of regulating neurogenesis directly in vivo. To define neurogenetic regulation in the brain, we employed postnatal day 1 cerebellar cortex, which mainly comprises granule neurons and dividing precursors. A number of growth factors, including bFGF directly stimulate granule cell proliferation in vitro, raising the possibility that the factor regulates neurogenesis in vivo. High expression of bFGF and its receptor in neonatal cerebellum further supports this contention. To define effects in vivo, bFGF was injected into newborn rat subcutaneously. Eight hours after injection, mitosis in cerebellar homogenates was increased by 50%. A striking 4-fold increase in {dollar}rmlbrack sp3Hrbrack dT{dollar} incorporation was observed in isolated granule cells, indicating that granule neuroblasts were the major responsive population. Morphological examination indicated that bFGF promoted more granule precursors in S-phase of the mitotic cycle. In addition, bFGF elicited a 68% increase in {dollar}rmlbrack sp3Hrbrack dT{dollar} incorporation in hippocampus and greater than and 2.5-fold increase in pontine subventricular zone, regions containing dividing neural precursors. In contrast, incorporation was not changed in the basal pons or cerebral cortex, regions in which neurogenesis has ceased by P1.; To explore the possibility of a direct effect, the distribution of peripherally administered {dollar}rm 125sb{lcub}l-bFGF{rcub}{dollar} was examined. Radioactivity and intact 18kDa {dollar}rm 125sb{lcub}l-bFGF{rcub}{dollar} was recovered from the brain, suggesting that peripherally injected bFGF was localized in the brain tissue to elicit mitogenic effects. The enhanced mitosis by exogenous bFGF suggests that the factor may normally regulate neural development.; To define the role of endogenous bFGF in brain development, specific neutralizing antibody to bFGF was utilized. Four hours after intracranial Ab injection, mitosis was decreased in cerebellar and hippocampal homogenates by 40% and 62% respectively. Further analysis revealed that Immunoneutralization of endogenous bFGF reduced granule cell DNA synthesis by 50%, indicating that the factor normally regulates neurogenesis during brain formation.; In summary, peripherally administered bFGF was localized in the brain to directly stimulate neuroblast proliferation. Endogenous bFGF normally regulates neurogenesis, suggesting that neurogenesis in vivo is subject to the regulation of extracellular signals. Peripheral administration of growth factors may regulate CNS formation and promote functional recovery from nervous system diseases.