Molecular Mechanisms of Transcription, Regulation, and Development 
of the Neuroendocrine System 
POU domains have been identified, each ex- 
pressed in a unique pattern early in development 
and during organogenesis. 
Most POU-domain genes were widely ex- 
pressed in all levels of the neural tube (including 
the retina) during early development, and hybrid- 
ization in the ventricular (proliferative) zone of 
the neuroepithelium is evident for all four tran- 
scripts at all levels. The time course of anatomic 
restriction in the developing neural tube is 
distinct, and the patterns for each gene product 
tend to reflect the adult loci of expression. In 
addition, reactive transcripts for some of these 
genes are also expressed during mammalian 
neurogenesis. 
We have recently identified many additional 
family members in the brain and have obtained 
initial evidence that at least some members of the 
family can bind to specific elements in distinct 
classes of neuronally expressed genes. We find 
that neurally expressed POU-domain proteins 
can be considered to represent distinct related 
families, each of which binds to related, but dis- 
tinct, DNA response elements. Putative target 
genes have been identified for several of these 
factors, and analysis of their function has revealed 
both inhibitory and stimulatory domains. 
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 
impose variable patterns of gene activation, po- 
tentially contributing to the refinement of pheno- 
typic variance required in the central nervous 
system. One class of coregulators has been char- 
acterized by expression cloning techniques. 
Development of the neuroendocrine system is 
also initially regulated by post-transcriptional 
strategies. We have provided evidence that a gene 
of the neuroendocrine system, the calcitonin/ 
CGRP (calcitonin gene-related peptide) gene, 
contains genomic regions that represent discrete 
hormone-encoding domains. The ultimate ex- 
pression of these domains is dependent on alter- 
native RNA-processing events that differentially 
include or exclude specific exons encoding cer- 
tain components of polypeptide regulators in the 
mature mRNA products. The rat and human calci- 
tonin/CGRP genes contain six exons. More than 
95 percent of the mature transcripts in thyroid 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, which appears to reflect the 
actions of a specific regulatory machinery con- 
trolling post-transcriptional RNA splice acceptor 
choice. CGRP appears to be an important regula- 
tor of blood pressure. 
Current investigations continue to explore 
these novel aspects of transcriptional and 
post-transcriptional regulatory strategies in neu- 
roendocrine gene expression. Results may pro- 
vide new ways of studying the problem of 
organogenesis. 
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