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Journal of Neuroscience, Vol 14, 4656-4673, Copyright © 1994 by Society for Neuroscience
The developmental expression in rat of proteases furin, PC1, PC2, and carboxypeptidase E: implications for early maturation of proteolytic processing capacity
M Zheng, RD Streck, RE Scott, NG Seidah and JE Pintar
Department of Anatomy and Cell Biology, Columbia University College of Physicians and Surgeons, New York, New York 10032.
The genes encoding mammalian subtilisin-like endoproteases furin, PC1, and
PC2 have been isolated and are implicated in endoproteolytic cleavage of
precursor molecules, which is a key step in posttranslational maturation of
proproteins and neuropeptide precursors. Following endoproteolytic
cleavage, the carboxyl-terminal basic amino acid residues are removed by
carboxypeptidase E (CPE). We have examined the expression of these genes
during rat development by in situ hybridization and compared their
expression patterns to those of potential substrates. In the primitive
streak stage of embryogenesis (e7) furin is expressed in both endoderm and
mesoderm. This overall expression pattern is maintained until e10, when a
distinctly higher level of furin expression is observed in the heart and
liver primordia. In mid- and late gestational stages furin is broadly
expressed in the peripheral tissues, and, therefore, may contribute to the
proteolytic processing of numerous fetal proproteins, such as the
precursors for natriuretic factors in heart and IGF-II throughout the
embryo. In contrast, the expressions of PC1 and PC2 are initiated much
later (e13) and are mainly confined to the developing nervous system, but
with distinct spatial distributions. At midgestational ages, PC1 mRNA is
mainly expressed in the hypothalamus and peripheral ganglia, while PC2 is
expressed not only in these tissues but also in the thalamus, midbrain,
pons, medulla oblongata, cortical plate, and spinal cord. Besides
neuropeptide precursor processing in the nervous system, PC1 and PC2 may
also be involved in the proteolytic processing in additional regions as
evidenced by the finding that both PC1 and PC2 mRNAs are expressed in the
embryonic pituitary and pancreas. CPE mRNA is expressed in both neural
tissues and some non-neural tissues. In the developing nervous system, the
expression of CPE encompasses all the regions where PC1 and PC2 are
expressed and in fact includes most brain regions as neurogenesis proceeds.
CPE mRNA is also expressed in some peripheral tissues, such as the
embryonic heart and cartilage primordia, and in some cases its expression
overlaps with furin expression. Thus, CPE may functionally collaborate
during development with the subtilisin family of endoproteases in the
completion of proteolytic processing of neuropeptide precursors in the
nervous system and proproteins in the peripheral tissues. In the pituitary,
the endoproteolytic processing of polyfunctional precursor
proopiomelanocortin (POMC) occurs in a developmentally regulated manner. We
have shown that while PC2 mRNA is predominantly expressed in the
intermediate lobe in the adult, we observed an increased expression of PC2
mRNA in developing rat anterior lobe, peaking at early postnatal
stages.(ABSTRACT TRUNCATED AT 400 WORDS)
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