Insulin-like growth factor binding proteins in fetal rat mesencephalic cultures: regulation by fibroblast growth factor and insulin-like growth factor I.
In rat ventral mesencephalic cultures, IGF-I and bovine fibroblast growth factor (bFGF) act cooperatively to support the survival of dopaminergic neurons. To determine the potential role of IGFBPs in modulating the actions of IGF-I in the ventral mesencephalon, we identified the IGFBPs present in ventral mesencephalic cultures and examined their regulation by IGF-I and bFGF. In the absence of added growth factors, the major binding protein secreted from these cultures was IGFBP-2. Small amounts of IGFFBP-3 and IGFBP-4 were also detected. Addition of bFGF to the cultures increased the amounts of IGFBP-3 and IGFBP-4 released from the cells by 4.4 +/- 2.6 -fold (P < 0.1) and 11.5 +/- 3.5 -fold (P < 0.05), respectively. IGF-I, itself, had little effect on the production of IGFBPs, but when added together with bFGF increased the levels of IGFBP-3 and IGFBP-4 by 12.4 +/- 5.1 -fold (P < 0.05) and 27.4 +/- 5.3 -fold (P < 0.02), respectively. The stimulatory effect of bFGF and IGF-I on IGFBP production was apparent after a 2- to 3-day exposure of the mesencephalic cultures to the peptides. IGFBP-4, the most abundant IGFBP present in the cultures after 7 days of growth factor treatment, was immunocyto-chemically localized primarily to neurons, of which a subset were dopaminergic neurons. The addition of purified rat IGFBP-4 to the cultures in the absence of added growth factors had no effect on the survival of dopaminergic neurons, but when added with IGF-I potentiated the effect of IGF-I on neuronal survival. We propose that the up-regulation of IGFBP-4 by IGF-I and bFGF may serve to localize IGF-I to sites of action in the nervous system and thereby potentiate the neurotrophic actions of IGF-I.
Kummer
J L
JL
Department of Pharmacology, University of Colorado Health Sciences Center, Denver 80262, USA.
Zawada
W M
WM
Freed
C R
CR
Chernausek
S D
SD
Heidenreich
K A
KA
D000595:Amino Acid Sequence; D000818:Animals; D000941:Antigens / Q000235:genetics; D015153:Blotting, Western; D002417:Cattle; D002478:Cells, Cultured; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D007150:Immunohistochemistry; D018969:Insulin-Like Growth Factor Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008636:Mesencephalon / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics; D051381:Rats / Q000196:embryology
D000941:Antigens; D018969:Insulin-Like Growth Factor Binding Proteins; D010446:Peptide Fragments; D005346:Fibroblast Growth Factors; D007334:Insulin-Like Growth Factor I