Spop promotes skeletal development and homeostasis by positively regulating Ihh signaling

Hongchen Cai, Aimin Liu

Research output: Contribution to journalArticlepeer-review

46 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)14751-14756
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number51
StatePublished - Dec 20 2016

All Science Journal Classification (ASJC) codes

  • General


Dive into the research topics of 'Spop promotes skeletal development and homeostasis by positively regulating Ihh signaling'. Together they form a unique fingerprint.

Cite this