NEUROGENESIS IN NEONATAL RAT-BRAIN IS REGULATED BY PERIPHERAL INJECTION OF BASIC FIBROBLAST GROWTH-FACTOR (BFGF)

Many major diseases of human brain involve deficiencies of select neur onal populations. As one approach to repair, we examined regulation of neurogenesis directly in vivo, employing postnatal day 1 (P1) cerebel lar cortex, which is composed primarily of granule neurons and dividin g precursors. We focused on basic fibroblast growth factor (bFGF), whi ch stimulates precursor mitosis in culture and which is highly express ed in cerebellum during neurogenesis. Subcutaneous injection of bFGF i ncreased [H-3]thymidine ([H-3]dT) incorporation, a marker for DNA synt hesis, by 50% in whole cerebellar homogenates, suggesting that periphe rally administered factor altered ongoing neural proliferation. Furthe r, assay of isolated granule precursors revealed a 4-fold increase in [H-3]dT incorporation following in vivo bFGF treatment, indicating tha t granule neuroblasts were the major bFGF-responsive population. Morph ologic analysis indicated that twice as many granule precursors were i n S-phase of the mitotic cycle after peripheral bFGF. To determine whe ther other neurogenetic populations respond to peripheral bFGF, we exa mined additional brain regions in vivo. bFGF stimulated DNA synthesis by 68% in hippocampus, and by >250% in pontine subventricular zone (SV Z). In contrast, incorporation was not altered in basal pens or cerebr al cortex, regions in which neurogensis has already ceased. To define potential direct actions of peripherally administered factor, I-125-bF GF was used to study distribution. Intact 18 kDa I-125-bFGF was recove red from brain following peripheral injection, suggesting that the fac tor acted directly to stimulate mitosis in dividing neuroblasts. The s timulation of neuronal proliferation by exogenous bFGF suggests that t he factor normally regulates neurogenesis, and provides new therapeuti c approaches to promote functional recovery from nervous system diseas es. (C) 1996 Wiley-Liss, Inc.