induced in PC 12 cells by nerve growth factor 
(NGF). They have shown that NGF induces the 
immediate-early c-fos gene, which encodes a tran- 
scription factor, c-Fos. Other members of the Fos 
family are also induced. The c-Fos stimulates a sec- 
ond gene encoding tyrosine hydroxylase (TH), an 
enzyme that catalyzes the rate-limiting step in dopa- 
mine neurotransmitter synthesis. The group has 
shown that a binding site for c-Fos (in a complex 
with c-Jun) in the TH promoter is critical for TH 
gene activation by NGF. The c-Fos may be an inter- 
mediary for TH gene regulation by signals from the 
plasma membrane. The Ela protein of adenovirus- 5, 
which sequesters the tumor-suppressor protein Rb 
and related factors, was found to disrupt the neuro- 
nal phenotype of PC 1 2 . Dr. Ziff 's laboratory is study- 
ing the role of tumor-suppressor proteins and nu- 
clear proto-oncoproteins such as c-Fos and c-Myc in 
regulating neuronal differentiation. 
Investigator Louis F. Reichardt, Ph.D. (University 
of California, San Francisco) and his colleagues are 
investigating molecules in the extracellular environ- 
ment of neurons that regulate their survival and di- 
rect their development in vivo. One project seeks 
an understanding of the role of trophic factors in 
regulating neuronal survival and development. 
These are proteins that regulate the differentiation 
of several neuronal populations, including neurons 
that are important in cognition. A second project 
concerns molecules on the surfaces of cells and in 
the extracellular matrix that serve as substrates for 
guiding the growth of axons. These molecules play 
critical roles in establishing correct wiring of the 
nervous system. A third project is directed toward 
identifying molecules that direct neurons to form 
synapses with other cells. Synapses are the sites of 
information transfer between neurons, so these mol- 
ecules are also crucial in establishing correct wiring 
of the nervous system. All of these studies are poten- 
tially useful in understanding and developing treat- 
ments for many diseases and disorders that disrupt 
normal brain function. 
The laboratory of Assistant Investigator David J. 
Anderson, Ph.D. (California Institute of Technol- 
ogy) studies the development of the neural crest, a 
structure that generates the neurons and glia of the 
vertebrate peripheral nervous system. Candidate 
master regulatory genes, that may control early de- 
terminative steps in neural crest development, have 
been isolated by their homology to neurogenic de- 
termination genes in the fruit fly Drosophila. The 
regulation and function of these genes are being ex- 
plored in detail. The group has also isolated embry- 
onic precursors of chromaffin cells, the endocrine 
cells of the adrenal gland, and found that their devel- 
opment is controlled both by steroid hormones and 
by an internal clock. 
The electrical activity of nerve cells arises as a 
result of the complex but carefully orchestrated 
opening and closing of thousands of the special pro- 
tein molecules called ion channels. These are of five 
main types: sodium, potassium, calcium, chloride, 
and nonspecific cation channels, named according 
to the ions that can pass through the open channel. 
Their activity is regulated by their chemical and 
electrical environment. For example, a particular 
type of potassium channel that the laboratory of In- 
vestigator Paul R. Adams, Ph.D. (State University of 
New York at Stony Brook) studies is the M channel. 
It is opened by positive changes in membrane po- 
tential and by small increases in intracellular cal- 
cium. It is closed by neurotransmitters released by 
other nerve cells and by large increases in internal 
calcium. In combination with a plethora of other 
types of ion channels, it regulates the firing patterns 
of nerve cells. 
The research of Associate Investigator Richard W. 
Aldrich, Ph.D. (Stanford University) and his col- 
leagues is directed toward understanding the molec- 
ular mechanisms of electrical signaling in the ner- 
vous system. The molecular elements of electrical 
signaling are proteins that lie in the cell membrane 
and serve as ion channels. These proteins regulate 
the passage of electrical current into the cell in re- 
sponse to stimuli. In the past few years, work by the 
group has focused on the mechanisms whereby ion 
channels open and inactivate, or turn off, after exci- 
tation. They have found a number of specific regions 
in a particular channel protein that are involved in 
activation and inactivation, and have determined 
some of the biophysical mechanisms that underlie 
the operation of these proteins. 
Voltage-sensitive potassium channels represent a 
diverse group of ion channels found in most cell 
types studied in the animal and the plant kingdom. 
In the nervous system, they control excitability and 
modulate the strength of synaptic inputs; some of 
the potassium channels have been implicated in the 
processes of learning and memory. The first potas- 
sium channel was cloned in the laboratory of Inves- 
tigator Lily Y. Jan, Ph.D. (University of California, 
San Francisco) by exploiting Drosophila genetics. 
The initial molecular characterizations have pro- 
vided some clues to questions concerning potas- 
sium channel diversity and have revealed some of 
the structural elements involved in different chan- 
nel functions. 
The laboratory of Investigator Christopher Miller, 
Ph.D. (Brandeis University) is interested in the 
basic mechanisms by which ion channel proteins 
NEUROSCIENCE 379 
