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Spop promotes skeletal development and homeostasis by positively regulating Ihh signaling

Hongchen Cai1,2,3, Aimin Liu4,2,3

  • 1Department of Biology, Eberly College of Science, The Pennsylvania State University, University Park, PA 16802.

Proceedings of the National Academy of Sciences of the United States of America
|December 9, 2016
PubMed

Insights

Speckle-type POZ protein (Spop) is crucial for skeletal development by positively regulating Indian Hedgehog (Ihh) signaling. Loss of Spop impairs chondrocyte and osteoblast differentiation, leading to skeletal defects that are rescued by reducing Gli3 levels.

Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Genetics

Background:

  • Indian Hedgehog (Ihh) signaling is vital for skeletal development, mediated by Glioma-associated oncogene homolog (Gli) transcription factors.
  • Speckle-type POZ protein (Spop) has been implicated in negatively regulating Hedgehog (Hh) signaling by targeting Gli2 and Gli3 for degradation via the Cullin-3 (Cul3) ubiquitin ligase complex.

Purpose of the Study:

  • To investigate the role of Spop in skeletal development and its precise mechanism in regulating Ihh signaling.
  • To determine if Spop acts as a positive or negative regulator of Ihh pathway activity in vivo.

Main Methods:

  • Analysis of Spop-null mutant mice to assess skeletal phenotypes and gene expression.
  • Utilizing conditional mutants to study the effects of Spop loss in specific tissues.
  • Performing ubiquitination assays to confirm direct interaction and degradation of Gli3 by Spop.

Main Results:

  • Spop-null mice exhibited defects in chondrocyte and osteoblast differentiation.
  • Gli3, but not Gli2, levels were elevated in Spop mutants, with decreased expression of Ihh target genes (Ptch1, Pthlh), indicating impaired Hh signaling.
  • Reducing Gli3 dosage rescued the skeletal defects in Spop mutants, and Spop was shown to directly ubiquitinate and degrade Gli3.

Conclusions:

  • Spop acts as a positive regulator of Ihh signaling and is essential for normal skeletal development.
  • Spop-mediated degradation of Gli3 is a key mechanism controlling Ihh pathway activity during skeletal formation.
  • Loss of Spop function leads to brachydactyly and osteopenia, highlighting Spop's critical role in bone and cartilage development.
Keywords:
Gli3endochondral ossificationosteoporosisskeletal developmentubiquitin ligase

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