Control of Transcription by Transmembrane Signals 
c-fos appears to be a first step in the activation of 
a multistage gene expression program induced by 
NGF that can culminate in cell division or the 
induction of terminally differentiated functions. 
In our model neuronal cells, we have shown 
that neurotransmitters as well as growth factors 
can also induce the expression of c-Fos. It is ap- 
parent from this and other studies that c-Fos has a 
critical role in the adult nervous system, not just 
in neural development. We have shown that c-Fos 
induced by NGF can cooperate with other factors 
to induce the gene for tyrosine hydroxylase (TH) , 
an enzyme that catalyzes a critical step in the pro- 
duction of neurotransmitters in the catechol- 
amine family. This participation of c-Fos in TH 
control may allow a neuron to coordinate the pro- 
duction of catecholamine neurotransmitters with 
the activity of the neuron during its function in 
the nervous system. 
We have gone on to show that NGF induces 
other genes as well. One of these encodes peri- 
pherin, a neuron-specific intermediate filament 
protein that is present in the axons of peripheral 
neurons as a component of the neuronal cytoskel- 
eton. Our studies of the developing rat nervous 
system indicate that peripherin expression coin- 
cides with the final steps of neuronal maturation 
and acquisition of function. Thus the mecha- 
nisms that control peripherin expression appear 
to be quite distinct from those that control c-Fos 
or TH. 
Study of these mechanisms may give a clue to 
how cells permanently exit from the cell cycle 
and induce the expression of genes that they em- 
ploy after losing the capacity to proliferate. One 
event that may block exit from the cell cycle is 
the uncontrolled expression of c-myc, another 
growth factor-induced gene. It encodes a pro- 
tein, c-Myc, that is distantly related to c-Fos and 
has a specialized but poorly understood function 
in inducing cell proliferation. It is expressed at 
abnormally high levels in many tumors. We have 
identified a DNA nucleotide sequence to which 
c-Myc can bind and a protein partner of c-Myc 
that can stimulate its DNA binding. Studies of the 
complexes of c-Myc with DNA may reveal the role 
of c-Myc in normal cell proliferation and in 
tumori genesis. 
We find that c-Myc expression is elevated in the 
naturally occurring childhood brain tumor me- 
dulloblastoma, where it is accompanied by a 
block to differentiation. We also find that the 
transforming gene of adenovirus, Ela, like c- 
myc, can block the differentiation of our model 
neurons, mimicking the state of the tumor. 
We seek to understand how cells respond to 
growth factor signals by proliferating and how 
cells coordinate their final differentiation with 
their exit from the cell cycle. Future studies will 
emphasize the roles of transmembrane signaling 
in adult nervous system function. 
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