Molecular Studies of Neurotransmitter Transport and Regulation 
of Neural Gene Expression 
transporter genes underlie major psychiatric af- 
fective disorders. 
Other ongoing research in the laboratory has 
focused on genes encoding another class of im- 
portant synaptic molecules, neuropeptides. Us- 
ing the calcitonin/CGRP (calcitonin gene-regu- 
lated peptide) gene family as a model system, we 
are investigating the mechanisms that regulate 
the production and structural diversity of these 
peptide neurotransmitters. The peptides of the 
calcitonin/CGRP family are produced in discrete 
sets of neurons in the nervous system. We are 
looking for the specific signal sequences within 
the genes for these peptides that allow the gene 
to be turned on in these sets of neurons. In addi- 
tion we are determining which sequences are in- 
volved in regulating the amount of neuropeptide 
mRNA produced. Once these specific control se- 
quences are identified, our next step is to search 
for the protein factors that recognize the se- 
quences and influence gene expression. Thus we 
can use a molecular biologic approach to charac- 
terize the individual steps that combine to pro- 
duce complex neurobiologic processes. 
The diversity of products expressed from the 
calcitonin/CGRP gene family depends not only 
on the presence of multiple, independently regu- 
lated genes but also on the existence of alterna- 
tive, tissue-specific pathways for pre-mRNA 
processing. This processing is an important mech- 
anism in the control of the expression of RNA 
products from many eukaryotic genes. Numerous 
gene products in the nervous system are encoded 
within complex transcription units that generate 
multiple mRNAs by altering where in the gene 
the transcripts initiate, how they are spliced, or 
how they terminate. In the nervous system, these 
processes may be particularly important, because 
they increase the diversity of expression by al- 
lowing multiple products to be encoded by a sin- 
gle gene. We would like to know how the same 
nuclear RNA transcripts can be processed in alter- 
native ways in diff'erent cells to generate distinct 
products. One potential determinant of a process- 
ing choice is found within the primary RNA tran- 
script, either as a specific sequence or secondary 
structural feature. A second determinant is found 
in the enzymatic machinery that recognizes these 
structural features and targets the transcript to a 
particular processing pathway. We have contin- 
ued to generate a variety of mutated and hybrid 
genes and, by introducing these constructs into a 
variety of cell types, have identified regions criti- 
cal for splicing regulation. 
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