Regulation of neuron production during postnatal brain development: The role of basic fibroblast growth factor (bFGF)

The control of neuronal number is critical for brain architecture and function. Extensive studies in culture suggest that bFGF plays an important role in precursor mitosis. However, its potential roles in postnatal neuron production remain undefined. To address this, newborn rats received a single subcutaneous injection of bFGF at zero time, and BrdU 6 hours later.; In cerebellum, 72hrs later, the fraction of BrdU-labeled cells in the EGL increased by 46% without altering apoptotic cell number, indicating enhanced precursor proliferation. Moreover, bFGF increased BrdU-labeled cells by 100% and total granule cell density by 33% in the IGL. Since cerebellar volume also increased by 22%, bFGF-induced proliferation enhanced generation of total IGL neurons and increased cerebellar growth. These morphometric measures were corroborated independently by measuring DNA content: cerebellar DNA content increased 16% after bFGF injection, indicating increased neuron number. Furthermore, using DNA content as an index, total cerebellar cell number increased by bFGF and persisted beyond the neurogenetic period P21, normalizing after P35. Therefore, we conclude that bFGF injection increases granule neuron number and enhances cerebellar growth following mitotic stimulation.; In hippocampus, peripheral bFGF treatment increased total hippocampal cell number throughout adulthood, measured by DNA content. Moreover, at P22, both a two-fold increase in BrdU-positive cells and a 33% increase in absolute granule neurons in the dentate granule cell layer (GCL) were observed, indicating enhanced generation of neurons by increased levels of bFGF. Furthermore, in bFGF-knockout mice, hippocampal cell number was decreased at all ages, examined by DNA content. To define effects on both neurons and glia, total GCL cells and hippocampal GFAP-positive cells were counted at P21: there was a 30% decrease in both populations in mutant mice, indicating that bFGF is necessary for normal hippocampal neuronogenesis and gliogenesis. Therefore, we conclude that environmental levels of bFGF regulate neonatal hippocampal neuron production by enhanced precursor proliferation.; In summary, these results suggest that bFGF regulates postnatal cerebellar and hippocampal neuron production by controlling precursor proliferation. These data also suggest that neurogenetic precursors exhibit region- and developmental stage-specific responses to bFGF.