11beta-Hydroxysteroid dehydrogenase type 2 protects the neonatal cerebellum from deleterious effects of glucocorticoids.
11beta-Hydroxysteroid dehydrogenase type 2 is a glucocorticoid metabolizing enzyme that catalyzes rapid inactivation of corticosterone and cortisol to inert 11-keto derivatives. As 11beta-hydroxysteroid dehydrogenase type 2 is highly expressed in the developing brain, but not in the adult CNS, we hypothesized that it may represent a protective barrier to the deleterious actions of corticosteroids on proliferating cells. To test this hypothesis we have investigated the development and growth of the cerebellum in neonatal C57BL/6 mice and mice lacking 11beta-hydroxysteroid dehydrogenase type 2 (-/-). 11beta-Hydroxysteroid dehydrogenase type 2-/- mice had consistently lower body weight throughout the neonatal period, coupled with a smaller brain size although this was normalized when corrected for body weight. The cerebellar size was smaller in 11beta-hydroxysteroid dehydrogenase type 2-/- mice, due to decreases in size of both the molecular and internal granule layers. When exogenous corticosterone was administered to the pups between postnatal days 4 and 13, 11beta-hydroxysteroid dehydrogenase type 2(-/-) mice were more sensitive, showing further inhibition of cerebellar growth while the wildtype mice were not affected. Upon withdrawal of exogenous steroid, there was a rebound growth spurt so that at day 21 postnatally, the cerebellar size in 11beta-hydroxysteroid dehydrogenase type 2-/- mice was similar to untreated mice of the same genotype. Furthermore, 11beta-hydroxysteroid dehydrogenase type 2-/- mice had a delay in the attainment of neurodevelopmental landmarks such as negative geotaxis and eye opening. We therefore suggest that 11beta-hydroxysteroid dehydrogenase type 2 acts as to protect the developing nervous system from the deleterious consequences of glucocorticoid overexposure.
Holmes
M C
MC
Endocrinology Unit, Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK. Megan.Holmes@ed.ac.uk
Sangra
M
M
French
K L
KL
Whittle
I R
IR
Paterson
J
J
Mullins
J J
JJ
Seckl
J R
JR
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D001835:Body Weight / Q000502:physiology; D001921:Brain / Q000201:enzymology / Q000254:growth & development; D049109:Cell Proliferation; D002531:Cerebellum / Q000254:growth & development / Q000473:pathology / Q000502:physiology*; D003345:Corticosterone / Q000097:blood; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis; D005938:Glucocorticoids / Q000502:physiology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size / Q000502:physiology; D004856:Postural Balance / Q000502:physiology; D012018:Reflex / Q000502:physiology
D005904:Glial Fibrillary Acidic Protein; D005938:Glucocorticoids; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D003345:Corticosterone