Hedgehog signaling has a protective effect in glucocorticoid-induced mouse neonatal brain injury through an 11betaHSD2-dependent mechanism.
Glucocorticoids (GCs) are administered to human fetuses at risk of premature delivery and to infants with life-threatening respiratory and cardiac conditions. However, there are ongoing concerns about adverse effects of GC treatment on the developing human brain, although the precise molecular mechanisms underlying GC-induced brain injury are unclear. Here, we identified what we believe to be novel cross-antagonistic interactions of Sonic hedgehog (Shh) and GC signaling in proliferating mouse cerebellar granule neuron precursors (CGNPs). Chronic GC treatment (from P0 through P7) in mouse pups inhibited Shh-induced proliferation and upregulation of expression of N-myc, Gli1, and D-type cyclin protein in CGNPs. Conversely, acute GC treatment (on P7 only) caused transient apoptosis. Shh signaling antagonized these effects of GCs, in part by induction of 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2). Importantly, 11betaHSD2 antagonized the effects of the GCs corticosterone, hydrocortisone, and prednisolone, but not the synthetic GC dexamethasone. Our findings indicate that Shh signaling is protective in the setting of GC-induced mouse neonatal brain injury. Furthermore, they led us to propose that 11betaHSD2-sensitive GCs (e.g., hydrocortisone) should be used in preference to dexamethasone in neonatal human infants because of the potential for reduced neurotoxicity.
Heine
Vivi M
VM
Department of Pediatrics, Howard Hughes Medical Institute and Institute for Regeneration Medicine, UCSF, San Francisco, California, USA.
Rowitch
David H
DH
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects; D003907:Dexamethasone / Q000633:toxicity; D005938:Glucocorticoids / Q000633:toxicity*; D053823:Hedgehog Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL
D005938:Glucocorticoids; D053823:Hedgehog Proteins; C465570:Shh protein, mouse; D003907:Dexamethasone; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2