Hedgehog signaling has a protective effect in glucocorticoid-induced mouse neonatal brain injury through an 11βHSD2-dependent mechanism
Vivi M. Heine, David H. Rowitch
Vivi M. Heine, David H. Rowitch
Published January 26, 2009
Citation Information: J Clin Invest. 2009;119(2):267-277. https://doi.org/10.1172/JCI36376.
View: Text | PDF
Research Article

Hedgehog signaling has a protective effect in glucocorticoid-induced mouse neonatal brain injury through an 11βHSD2-dependent mechanism

Abstract

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 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2). Importantly, 11βHSD2 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 11βHSD2-sensitive GCs (e.g., hydrocortisone) should be used in preference to dexamethasone in neonatal human infants because of the potential for reduced neurotoxicity.

Authors

Vivi M. Heine, David H. Rowitch

×

Figure 5

Shh signaling upregulates transcription of 11βHSD2 in vitro and in vivo.

Options: View larger image (or click on image) Download as PowerPoint
Shh signaling upregulates transcription of 11βHSD2 in vitro and in vivo....
(A) Whole RNA was isolated from WT and Math1cre,SmoM2 CGNP cultures treated with vehicle, Shh, or Shh plus 40 μM Dex for 24 h. Quantitative PCR analysis showed that Shh treatment potently induced the Shh targets N-myc and Gli1 as well as 11βHSD2 expression in WT CGNP cultures. Math1cre,SmoM2 CGNPs showed increased expression of N-myc, Gli1, and 11βHSD2 in both vehicle and Shh groups and was unchanged after Dex treatment. 11βHSD1 expression was below detectable levels. (B) In vivo, N-myc, Gli1, and 11βHSD2 levels were upregulated in the Math1cre,SmoM2 cerebellum (CB). (C) In situ hybridization showing specific expression of 11βHSD2 in the EGL of the P7 WT and Math1cre,SmoM2 cerebellum. Original magnification, ×400.