neuroendocrine system. The rat calcitonin/CGRP 
gene contains six exons; splicing of the first four 
exons generates calcitonin mRNA, which represents 
>98% of mature transcripts of this gene in thyroid 
C cells. In contrast, in the brain and peripheral ner- 
vous system, the first three exons are spliced to the 
fifth and sixth exons, generating the mRNA encod- 
ing the precursor of the novel 37-amino acid neu- 
ropeptide, CGRE 
The developmental regulation of alternative exon 
usage in calcitonin/CGRP gene expression is associ- 
ated with the utilization of alternative poly(A) sites 
within a single transcription unit. Introduction of 
the rat calcitonin/CGRP gene under transcriptional 
regulation of the mouse metallothionein I pro- 
moter into fertilized mouse eggs resulted in trans- 
genic animals that expressed calcitonin mRNA as 
the predominant mature transcript in all tissues not 
expressing the endogenous calcitonin/CGRP gene, 
except brain. In the central nervous system, CGRP 
mRNA was the predominant transcript in many 
neurons not expressing the endogenous gene. A 
few neurons produced calcitonin mRNA. These 
PUBLICATIONS 
data suggest that calcitonin mRNA is the unregu- 
lated choice and that specific RNA processing 
machinery, predominantly localized to the central 
nervous system, is required for CGRP mRNA pro- 
duction. A family of snRNPs (small nuclear ribo- 
nucleoproteins) expressed in cells capable of gen- 
erating the CGRP transcript do not appear 
sufficient to mediate the observed cell-specific RNA- 
splicing choices. Cell lines that mimicked the be- 
havior of neural and endocrine tissues expressing 
the endogenous gene have been identified and 
used for DNA-mediated gene transfer of the un- 
modified and mutated calcitonin/CGRP gene. These 
studies have generated evidence supporting a 
model that predicts that cell-specific differences in 
splice acceptor choice, mediated by the action of an 
inhibitory neuronal factor, are the developmentally 
regulated events that unexpectedly dictate alterna- 
tive splice acceptor choice. 
Dr. Rosenfeld is also Professor of Medicine, Eu- 
karyotic Regulatory Biology Program, University of 
California School of Medicine at San Diego. 
Books and Chapters of Books 
Rosenfeld, M.G. 1988. Molecular determinants of positive and negative regulation by ligand-regulated tran- 
scription factors. In Steroid Receptors in Health and Disease. New York: Plenum, pp 163-176. 
Rosenfeld, M.G., Crenshaw, E.B., III, Emeson, R.B., Leff S., Lira, S., Nelson, C, and Russo, A. 1988. Transcrip- 
tional and post-transcriptional strategies in neuroendocrine gene expression. In Developmental Biology: 
A Comprehensive Synthesis (Browder, L.W, Ed.). New York: Plenum, vol 5, pp 317-334. 
Articles 
Crenshaw, E.B., III , Kalla, K., Simmons, D.M., Swanson, L.W, and Rosenfeld, M.G. 1989. Cell-specific expres- 
sion of the prolactin gene in transgenic mice is controlled by synergistic interactions between promoter 
and enhancer elements. Genes Dev 3:959-972. 
Gill, G.N., Chen, WS., Lazar, C.S., Glenney, J.R., Jr., Wiley H.S., Ingraham, H.A. , and Rosenfeld, M.G. 1988. 
Role of intrinsic protein tyrosine kinase in function and metabolism of the epidermal growth factor recep- 
tor. Cold Spring Harb Symp Quant Biol 53:467-476. 
Hanson, P., Kapiloff, M.S., Lou, L.L., Rosenfeld, M.G., and Schulman, H. 1989. Expression of a multifunctional 
Ca''""'"/calmodulin-dependent protein and mutational analysis of its autoregulation. Neuron 3:9-70. 
He, X., Treacy, M.N., Simmons, D.M., Ingraham, H.A., Swanson, L.W, and Rosenfeld, M.G. 1989. Expression of 
a large family of POU-domain regulatory genes in mammalian brain development. Nature 340:35-41. 
Herr, W, Sturm, R.A., Clerc, R.G., Corcoran, L.M., Baltimore, D., Sharp, P, Ingraham, H.A., Rosenfeld, M.G., 
Finney, M., Ruvkun, G., and Horvitz, H.R. 1988. The POU domain: a large conserved region in the mamma- 
lian pit-\, oct-1, oct-2, and Caenorhabditis elegans unc-86 gene products. Genes Dev 2:1513-1516. 
Ingraham, H.A. , Chen, R., Mangalam, H.J., Elsholtz, H.P , Flynn, S.E., Lin, C.R., Simmons, D.M., Swanson, L., 
and Rosenfeld, M.G. 1988. A tissue-specific transcription factor containing a homeodomain specifies a pi- 
tuitary phenotype. Ce// 55:519-529. 
Continued 
527 
