Ventral specification and perturbed boundary formation in the mouse midbrain in the absence of Hedgehog signaling

Although Hedgehog (HH) signaling plays a critical role in patterning the ventral midbrain, its role in early midbrain specification is not known. We examined the midbrains of sonic hedgehog ( Shh ) and smoothened ( Smo ) mutant mice where HH signaling is respectively attenuated and eliminated. We show that some ventral ( Evx1+ ) cell fates are specified in the Shh −/− mouse in a Ptc1 ‐ and Gli1 ‐independent manner. HH‐independent ventral midbrain induction was further confirmed by the presence of a Pax7 ‐negative ventral midbrain territory in both Shh −/− and Smo −/− mice at and before embryonic day (E) 8.5. Midbrain signaling centers are severely disrupted in the Shh −/− mutant. Interestingly, dorsal markers are up‐regulated ( Wnt1 , Gdf7 , Pax7 ), down‐regulated ( Lfng ), or otherwise altered ( Zic1 ) in the Shh −/− midbrain. Together with the increased cell death seen specifically in Shh −/− dorsal midbrains (E8.5–E9), our results suggest specific regulation of dorsal patterning by SHH, rather than a simple deregulation due to its absence. Developmental Dynamics 237:1359‐1372, 2008. © 2008 Wiley‐Liss, Inc.