Novel expression of the tyrosine hydroxylase gene requires both acidic fibroblast growth factor and an activator.
Substances found in the soluble extract of muscle can alter the differentiative fate of certain brain neurons in culture by triggering novel expression of the gene for the catecholamine biosynthetic enzyme tyrosine hydroxylase (TH) (Iacovitti et al., 1989; Iacovitt, 1991). In this study, we demonstrate that TH induction in cultured noncatecholamine neurons from the mouse striatum requires the cooperative interaction of at least two substances found in muscle. Purification studies, combined with biological assay, revealed that one necessary component is acidic fibroblast growth factor (aFGF), and the other, an unidentified molecule(s) of < 10 kDa molecular weight that activated aFGF. Thus, muscle-derived aFGF, if incubated in the presence but not the absence of the < 10 kDa fraction of muscle, induced a dose-dependent increase in the number of striatal neurons that novelly express TH. This expression was blocked by prior incubation and protein A precipitation of the factor with polyclonal antibodies to aFGF (1:200-1:1000). Similar to muscle-purified aFGF, commercial preparations of native bovine and human recombinant aFGF (0.1-100 ng/ml) were potent inducers of TH when coincubated with the < 10 kDa activator. In contrast, basic FGF produced little and FGF-7 no induction of TH. Unlike the unidentified activating agent in muscle, heparin (20-500 mU), a known activator of aFGF, did not potentiate the factor's TH-inducing activity. Nonetheless, heparatinase (100 mU) prevented TH induction by aFGF and its activator, indicating that binding of heparan sulfated proteoglycans is necessary for the effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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Department of Neurology, Hahnemann University, Philadelphia, Pennsylvania 19102-1192.
Stull
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Iacovitti
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D000818:Animals; D002417:Cattle; D002999:Clone Cells; D004790:Enzyme Induction; D016220:Fibroblast Growth Factor 1 / Q000494:pharmacology / Q000502:physiology*; D005346:Fibroblast Growth Factors / Q000145:classification / Q000494:pharmacology; D015870:Gene Expression; D009132:Muscles / Q000166:cytology / Q000502:physiology; D051381:Rats; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics*
D016220:Fibroblast Growth Factor 1; D005346:Fibroblast Growth Factors; D014446:Tyrosine 3-Monooxygenase