The human skeleton provides essential mechanical support, mobility, and mineral storage critical for health ( 1). In summary, Spop is an important positive regulator of Ihh signaling and skeletal development. 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. We further show that Spop directly targets the Gli3 repressor for ubiquitination and degradation. Consistent with this finding, reducing Gli3 dosage greatly rescued the Spop mutant skeletal defects. 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. In this study, we found defects in chondrocyte and osteoblast differentiation in Spop-null mutant mice. 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. Indian Hedgehog (Ihh) regulates chondrocyte and osteoblast differentiation through the Glioma-associated oncogene homolog (Gli) transcription factors.
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