Distinct ontogeny of glucocorticoid and mineralocorticoid receptor and 11beta-hydroxysteroid dehydrogenase types I and II mRNAs in the fetal rat brain suggest a complex control of glucocorticoid actions

Abstract

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 11beta-hydroxysteroid dehydrogenases (11beta-HSDs) that catalyze the interconversion of active corticosterone and inert 11-dehydrocorticosterone. 11beta-HSD type 1 (11beta-HSD1) is a bidirectional enzyme in vitro that acts predominantly as a reductase (regenerating corticosterone) in intact neurons. In contrast, 11beta-HSD type 2 (11beta-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 11beta-HSD mRNAs and enzyme activity during prenatal brain development and correlated this with GR and MR mRNA development. These data reveal that (1) 11beta-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) 11beta-HSD2-like activity parallels closely the pattern of mRNA expression; (3) 11beta-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 11beta-HSD2 at midgestation may protect the developing brain from activation of GR by GCs. Late in gestation, repression of 11beta-HSD2 gene expression may allow increasing GC activation of GR and MR, permitting key GC-dependent neuronal and glial maturational events.

Fig. 1.

Expression of 11β-HSD type 2 and 11β-HSD type 1 in the rat brain from E11.5 to E15.5. Results of in situ hybridization for 11β-HSD TYPE 2 and 11β-HSD TYPE 1 are shown from left toright, respectively, for each gestation. The following are labeled in Figures 1-5: 1, extraembryonic membrane;2, hippocampal (Ammon’s horn) and subicular regions;3, neocortex; 4, septum;5, liver; 6, dorsal mesencephalon;7, pontine area; 8, intermediate, mammillary, and posterior hypothalamic areas; 9, hypothalamus and anterior hypothalamus; 10, tegmental area; 11, intermediate thalamus; 12, medulla; 13, spinal cord; 14, dorsal diencephalon; 15, cerebellum; 16, pituitary; 17, uterine wall; 18, taenia tecta; 19, indesium griseum; 20, cingulate cortex; 21, lamina terminalis;22, epithalamus; 23, pretectum;24, ventral hypothalamus; 25, preoptic area; 26, thalamus; 26a, posterior thalamus and epithalamus; 26b, thalamus and anterior-medial area; 27, mammillary area;28, posterior hypothalamus; 29, ventral isthmal area; 30, inferior colliculus;31, superior colliculus; 32, dorsal isthmal area; 33, precerebellar area; 34, basal ganglia and strionuclear area; 35, pallidum;36, arcuate nucleus and ventral medial hypothalamus;37, posterior thalamus; 38, anterior thalamus; 39, olfactory bulb; 40, locus coerulus; 41, anterior pontine area; 42, posterior pontine area; 43, dorsal raphe;44, pineal gland; 45, choroid plexus and lateral ventricle; 46, skin; 47, precerebellar area and above choroid plexus; and 48, dorsal periaqueductal gray and superior colliculus.

Fig. 2.

Expression of GR and MR in the rat brain from E11.5 to E15.5. Results of in situ hybridization forGR and MR are shown fromleft to right, respectively, for each gestation. For labeling of regions see text of Figure 1.

Fig. 3.

Expression of 11β-HSD type 2 and 11β-HSD type 1 in the rat brain from E16.5 to E20.5. Results of in situ hybridization for 11β-HSD TYPE 2 and 11β-HSD TYPE 1 are shown from left toright, respectively, for each gestation. For labeling of regions see text of Figure 1.

Fig. 4.

Expression of GR and MR in the rat brain from E16.5 to E20.5. Results of in situ hybridization forGR and MR are shown fromleft to right, respectively, for each gestation. For labeling of regions see text of Figure 1.

Fig. 5.

Expression of GR,MR, 11β-HSD TYPE 2, and 11β-HSDTYPE 1 mRNAs in the rat brain at E22.5. For labeling of regions see text of Figure 1.

Fig. 6.

Expression of GR,MR, 11β-HSD TYPE 2, and 11β-HSDTYPE 1 mRNAs in the rat hippocampus at E22.5. The following regions are labeled in the figure: striatum (st); lateral ventricle (lv); hippocampus (hr); dorsal hippocampus (dh); ventral hippocampus (vh); and piriform cortex (pc).  Arrows indicate skin tissue.

Fig. 7.

11β-Dehydrogenase activity from homogenates of rat brain tissue (A) and placenta (B) at ages E12.5, E14.5, E17.5, and E20.5. Cosubstrates were added at 100 μm. Note the predominant NAD⁺-dependent reaction, typical of 11β-HSD2.