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

Dev Dyn. 2008 May;237(5):1359-72. doi: 10.1002/dvdy.21536.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Lineage
  • Female
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism*
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism
  • Mesencephalon / anatomy & histology*
  • Mesencephalon / embryology
  • Mesencephalon / metabolism*
  • Mice
  • Mice, Knockout
  • Morphogenesis*
  • Neurons / cytology
  • Neurons / metabolism
  • Patched Receptors
  • Patched-1 Receptor
  • Pregnancy
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction / physiology*
  • Smoothened Receptor
  • Zinc Finger Protein GLI1

Substances

  • Gli1 protein, mouse
  • Hedgehog Proteins
  • Kruppel-Like Transcription Factors
  • Patched Receptors
  • Patched-1 Receptor
  • Ptch1 protein, mouse
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • Shh protein, mouse
  • Smo protein, mouse
  • Smoothened Receptor
  • Zinc Finger Protein GLI1