期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：51
页码：14751-14756
DOI：10.1073/pnas.1612520114
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceSkeletal diseases place a huge burden on patients and society, and yet their genetic basis remains poorly understood. In this article, we identify Speckle-type POZ protein (Spop) as a regulator of skeletal development, loss of which leads to shorter digit bones and lower bone density. We also show that, in striking contrast to the current dogma positing Spop as a negative regulator of Hedgehog (Hh) signaling, Spop regulates skeletal development by promoting Indian Hedgehog (Ihh) signaling. Therefore, our work represents an important conceptual advance in the understanding of Ihh signaling and skeletal development and provides a potential new target for the diagnosis and intervention of bone diseases such as osteoporosis. 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.
