Molecular Mechanisms of Olfaction 
zymes and novel ion channels play important 
roles in this process. We have identified cDNA 
clones encoding three distinct forms of adenylyl 
cyclase and are investigating the regulation of 
this important enzyme in olfactory tissue. It ap- 
pears that one form of this enzyme is expressed 
by olfactory sensory neurons. This olfactory neu- 
ronal adenylyl cyclase, type III, has biochemical 
properties that w^ould be advantageous for an en- 
zyme involved in sensory transduction. Electro- 
physiologic experiments have identified cyclic 
nucleotide-gated ion channels in olfactory neu- 
rons, and we have recently isolated and charac- 
terized cDNA clones from olfactory tissue that en- 
code ion channels with properties similar to 
those found in the visual system. 
The olfactory system is also interesting as a 
model for neuron differentiation and develop- 
ment. The olfactory neuroepithelium is the only 
neuronal tissue in adult mammals that undergoes 
continual regeneration. The lifetime of sensory 
neurons is approximately 40 days, after which 
they are shed from the epithelium and replaced 
from a population of neuroblast-like precursor 
cells. Moreover, if the nerve leading from the sen- 
sory neurons to the olfactory bulb is severed, all 
1 0 million receptor cells are rapidly lost and sub- 
sequently replaced in a relatively synchronous 
fashion. 
We have recently identified a number of cDNA 
clones that encode proteins expressed only in the 
mature sensory neurons and are presently at- 
tempting to elucidate their role in the cell. A 
novel group of proteins, those expressed tran- 
siently during neuron maturation, may include 
receptors for neurogenic as well as neurotrophic 
factors. Several of the genes we have identified 
appear to encode membrane-bound or cell sur- 
face proteins. 
We have also initiated a project to generate cell 
lines derived from cells of olfactory neuronal lin- 
eage. Transgenic mice have been identified that 
carry the SV40 T antigen oncogene linked to a 
transcriptional promoter for an abundant olfac- 
tory neuron-specific gene product. These animals 
develop tumors originating in the olfactory neu- 
roepithelium. From these tumors, we have estab- 
lished cell lines in culture that express a number 
of characteristic neuronal markers. These cell 
lines express several ; of the neuron-specific 
markers we previously identified. This approach 
may be generally applicable to the isolation of 
defined cell lines in many other systems. 
We are continuing to use several techniques to 
elucidate the mechanism of signal transduction. 
Likewise, the identification of proteins asso- 
ciated with the replacement of olfactory neurons 
provides the tools to study neural development, 
not just in the olfactory system but also in other 
areas of the brain. In the future, we will focus on 
the molecular components that underlie the 
complex mechanisms of signal transduction, sig- 
nal processing, and the formation of neural 
connections. 
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