Journal of Neuroscience, Vol 14, 7688-7694, Copyright © 1994 by Society for Neuroscience
Novel expression of the tyrosine hydroxylase gene requires both acidic fibroblast growth factor and an activator
X Du, ND Stull and L Iacovitti
Department of Neurology, Hahnemann University, Philadelphia, Pennsylvania 19102-1192.
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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