Hedgehog signaling has a protective effect in glucocorticoid-induced mouse neonatal brain injury through an 11betaHSD2-dependent mechanism

Vivi M Heine, David H Rowitch

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105 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)267-77
Number of pages11
JournalJournal of clinical investigation
Issue number2
Publication statusPublished - Feb 2009


  • 11-beta-Hydroxysteroid Dehydrogenase Type 2/physiology
  • Animals
  • Animals, Newborn
  • Apoptosis/drug effects
  • Brain/drug effects
  • Cell Proliferation/drug effects
  • Cells, Cultured
  • Cerebellum/drug effects
  • Dexamethasone/toxicity
  • Glucocorticoids/toxicity
  • Hedgehog Proteins/physiology
  • Mice
  • Mice, Inbred C57BL

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