Spop promotes skeletal development and homeostasis by positively regulating Ihh signaling

Proc Natl Acad Sci U S A. 2016 Dec 20;113(51):14751-14756. doi: 10.1073/pnas.1612520114. Epub 2016 Dec 5.


Indian Hedgehog (Ihh) regulates chondrocyte and osteoblast differentiation through the Glioma-associated oncogene homolog (Gli) transcription factors. Previous in vitro studies suggested that Speckle-type POZ protein (Spop), part of the Cullin-3 (Cul3) ubiquitin ligase complex, targets Gli2 and Gli3 for degradation and negatively regulates Hedgehog (Hh) signaling. In this study, we found defects in chondrocyte and osteoblast differentiation in Spop-null mutant mice. Strikingly, both the full-length and repressor forms of Gli3, but not Gli2, were up-regulated in Spop mutants, and Ihh target genes Patched 1 (Ptch1) and parathyroid hormone-like peptide (Pthlh) were down-regulated, indicating compromised Hh signaling. Consistent with this finding, reducing Gli3 dosage greatly rescued the Spop mutant skeletal defects. We further show that Spop directly targets the Gli3 repressor for ubiquitination and degradation. Finally, we demonstrate in a conditional mutant that loss of Spop results in brachydactyly and osteopenia, which can be rescued by reducing the dosage of Gli3. In summary, Spop is an important positive regulator of Ihh signaling and skeletal development.

Keywords: Gli3; endochondral ossification; osteoporosis; skeletal development; ubiquitin ligase.

Publication types

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

MeSH terms

  • Animals
  • Bone and Bones / embryology*
  • Bone and Bones / pathology*
  • Cell Differentiation
  • Chondrocytes / metabolism
  • Crosses, Genetic
  • Gene Expression Regulation, Developmental
  • Genes, Reporter
  • Hedgehog Proteins / metabolism*
  • Heterozygote
  • Kruppel-Like Transcription Factors / metabolism
  • Lac Operon
  • Mice
  • Nerve Tissue Proteins / metabolism
  • Nuclear Proteins / metabolism*
  • Osteoporosis / metabolism
  • Repressor Proteins / metabolism*
  • Signal Transduction
  • Ubiquitin-Protein Ligase Complexes
  • Ubiquitin-Protein Ligases / metabolism
  • Zinc Finger Protein Gli3 / metabolism


  • Gli3 protein, mouse
  • Hedgehog Proteins
  • Kruppel-Like Transcription Factors
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Repressor Proteins
  • Zinc Finger Protein Gli3
  • ihh protein, mouse
  • Spop protein, mouse
  • Ubiquitin-Protein Ligase Complexes
  • Ubiquitin-Protein Ligases