title: Spop promotes skeletal development and homeostasis by positively regulating Ihh signaling.
abstract: 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.
authors.affiliation: Department of Biology, Eberly College of Science, The Pennsylvania State University, University Park, PA 16802.|Center for Cellular Dynamics, Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA 16802.|Center for Molecular Investigation of Neurological Disorders, Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA 16802.
authors.forename: Hongchen
authors.initials: H
authors.lastname: Cai
authors.affiliation: Department of Biology, Eberly College of Science, The Pennsylvania State University, University Park, PA 16802; axl25@psu.edu.|Center for Cellular Dynamics, Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA 16802.|Center for Molecular Investigation of Neurological Disorders, Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA 16802.
authors.forename: Aimin
authors.initials: A
authors.lastname: Liu
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000196:embryology* / Q000473:pathology*; D002454:Cell Differentiation; D019902:Chondrocytes / Q000378:metabolism; D003433:Crosses, Genetic; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D053823:Hedgehog Proteins / Q000378:metabolism*; D006579:Heterozygote; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D007763:Lac Operon; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D010024:Osteoporosis / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D043743:Ubiquitin-Protein Ligase Complexes; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000074290:Zinc Finger Protein Gli3 / Q000378:metabolism
chemical_list: C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D000074290:Zinc Finger Protein Gli3; C514061:ihh protein, mouse; C509762:Spop protein, mouse; D043743:Ubiquitin-Protein Ligase Complexes; D044767:Ubiquitin-Protein Ligases
keywords: Gli3; endochondral ossification; osteoporosis; skeletal development; ubiquitin ligase