Determinants of Developmental Programs of Gene Activation 
the neuroepithelium was evident for all four 
transcripts at all levels. The time course of ana- 
tomic restriction in the developing neural tube 
was distinct, and the patterns for each gene prod- 
uct tended to reflect the adult loci of expression. 
In addition, reactive transcripts for some of these 
geftes were also expressed during mammalian 
neurogenesis. We recently identified many addi- 
tional family members in the brain and obtained 
evidence that at least some members of this fam- 
ily can bind to specific elements in distinct 
classes of neuronally expressed genes. Two POU- 
domain genes were cloned from Drosophila 
cDNA libraries and identified in neural structures 
during development. These proteins form stable 
heterodimers and act to alter patterns of activa- 
tion of neuron-specific genes. 
Interactions between diverse transcription fac- 
tors generate heterodimers that exert distinct pat- 
terns of gene activation. Thus, in the case of the 
retinoic acid receptor, we find that a series of cell 
type-specific coregulators impose novel hierar- 
chies of binding site preferences. Unique posi- 
tive and negative transcriptional regulators im- 
pose variable patterns of gene activation, 
potentially contributing to the refinement of phe- 
notypic variance required in the central nervous 
system. 
We have provided evidence that a gene of the 
neuroendocrine system, the calcitonin/calci- 
tonin gene-related peptide (CGRP) gene, con- 
tains genomic regions that represent discrete 
hormone-encoding domains. The ultimate ex- 
pression of these domains depends on alternative 
RNA-processing events that differentially include 
or exclude specific exons encoding specific com- 
ponents of polypeptide regulators in the mature 
mRNA products. The rat and human calcitonin/ 
CGRP genes are composed of six exons. More 
than 95 percent of the mature transcripts in thy- 
roid C cells, encoding calcitonin, are produced 
by splicing of the first three to four exons. CGRP 
mRNA is the only detectable mature transcript in 
rat neuronal tissue. This appears to reflect the 
actions of a specific regulatory machinery con- 
trolling post-transcriptional RNA splice acceptor 
choice, dependent on a specific, discrete cis- 
active element. 
In summary, these investigations have estab- 
lished several novel aspects of transcriptional 
and post-transcriptional regulatory strategies 
in neuroendocrine gene expression and in 
organogenesis. 
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