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The Journal of Neuroscience, April 1, 1998, 18(7):2570-2580
Distinct Ontogeny of Glucocorticoid and Mineralocorticoid
Receptor and 11 -Hydroxysteroid Dehydrogenase Types I and II mRNAs in
the Fetal Rat Brain Suggest a Complex Control of Glucocorticoid
Actions
Rochellys
Diaz,
Roger W.
Brown, and
Jonathan R.
Seckl
Molecular Medicine Centre, Western General Hospital, University of
Edinburgh, Edinburgh EH4 2XU, United Kingdom
Glucocorticoids (GCs) act via intracellular mineralocorticoid (MR)
and glucocorticoid receptors (GR). However, it has recently been
recognized that GC access to receptors is determined by the presence of
tissue-specific 11 -hydroxysteroid dehydrogenases (11-HSDs) that
catalyze the interconversion of active corticosterone and inert
11-dehydrocorticosterone. 11-HSD type 1 (11-HSD1) is a
bidirectional enzyme in vitro that acts predominantly as a reductase (regenerating corticosterone) in intact neurons. In contrast, 11-HSD type 2 (11-HSD2) is a higher affinity exclusive dehydrogenase that excludes GCs from MR in the kidney, producing aldosterone-selectivity in vivo. We have examined the
ontogeny of 11-HSD mRNAs and enzyme activity during prenatal brain
development and correlated this with GR and MR mRNA development. These
data reveal that (1) 11-HSD2 mRNA is highly expressed in all CNS
regions during midgestation, but expression is dramatically reduced
during the third trimester except in the thalamus and cerebellum; (2) 11-HSD2-like activity parallels closely the pattern of mRNA
expression; (3) 11-HSD1 mRNA is absent from the CNS until the the
third trimester, and activity is low or undectectable; and (4) GR mRNA
is highly expressed throughout the brain from midgestation, but MR gene expression is absent until the last few days of gestation. High 11-HSD2 at midgestation may protect the developing brain from activation of GR by GCs. Late in gestation, repression of 11-HSD2 gene expression may allow increasing GC activation of GR and MR, permitting key GC-dependent neuronal and glial maturational events.
Key words:
11-hydroxysteroid dehydrogenases; glucocorticoid
receptor; mineralocorticoid receptor; ontogeny; fetal brain; rats
Copyright © 1998 Society for Neuroscience 0270-6474/98/1872570-11$05.00/0
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