Spop Promotes Skeletal Development and Homeostasis by Positively Regulating Ihh Signaling

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2016 Dec 9

PMID 27930311

Citations 39

Authors

Hongchen Cai

Aimin Liu

Affiliations

Soon will be listed here.

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.

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References

Wang B, Fallon J, Beachy P . Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell. 2000; 100(4):423-34. DOI: 10.1016/s0092-8674(00)80678-9. View

Temtamy S, Aglan M . Brachydactyly. Orphanet J Rare Dis. 2008; 3:15. PMC: 2441618. DOI: 10.1186/1750-1172-3-15. View

Karp S, Schipani E, St-Jacques B, Hunzelman J, Kronenberg H, McMahon A . Indian hedgehog coordinates endochondral bone growth and morphogenesis via parathyroid hormone related-protein-dependent and -independent pathways. Development. 2000; 127(3):543-8. DOI: 10.1242/dev.127.3.543. View

Long F . Building strong bones: molecular regulation of the osteoblast lineage. Nat Rev Mol Cell Biol. 2011; 13(1):27-38. DOI: 10.1038/nrm3254. View

Hilton M, Tu X, Cook J, Hu H, Long F . Ihh controls cartilage development by antagonizing Gli3, but requires additional effectors to regulate osteoblast and vascular development. Development. 2005; 132(19):4339-51. DOI: 10.1242/dev.02025. View

Pan Y, Wang B . A novel protein-processing domain in Gli2 and Gli3 differentially blocks complete protein degradation by the proteasome. J Biol Chem. 2007; 282(15):10846-52. DOI: 10.1074/jbc.M608599200. View

Claiborn K, Sachdeva M, Cannon C, Groff D, Singer J, Stoffers D . Pcif1 modulates Pdx1 protein stability and pancreatic β cell function and survival in mice. J Clin Invest. 2010; 120(10):3713-21. PMC: 2947215. DOI: 10.1172/JCI40440. View

Pan Y, Bai C, Joyner A, Wang B . Sonic hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation. Mol Cell Biol. 2006; 26(9):3365-77. PMC: 1447407. DOI: 10.1128/MCB.26.9.3365-3377.2006. View

Zhang Q, Zhang L, Wang B, Ou C, Chien C, Jiang J . A hedgehog-induced BTB protein modulates hedgehog signaling by degrading Ci/Gli transcription factor. Dev Cell. 2006; 10(6):719-29. DOI: 10.1016/j.devcel.2006.05.004. View

10.

Logan M, Martin J, Nagy A, Lobe C, Olson E, Tabin C . Expression of Cre Recombinase in the developing mouse limb bud driven by a Prxl enhancer. Genesis. 2002; 33(2):77-80. DOI: 10.1002/gene.10092. View

11.

Hsu S, Zhang X, Cheng S, Wunder J, Hui C, Alman B . Suppressor of fused (Sufu) mediates the effect of parathyroid hormone-like hormone (Pthlh) on chondrocyte differentiation in the growth plate. J Biol Chem. 2012; 287(43):36222-8. PMC: 3476289. DOI: 10.1074/jbc.M112.382275. View

12.

Wang C, Pan Y, Wang B . Suppressor of fused and Spop regulate the stability, processing and function of Gli2 and Gli3 full-length activators but not their repressors. Development. 2010; 137(12):2001-9. PMC: 2875842. DOI: 10.1242/dev.052126. View

13.

Mackie E, Tatarczuch L, Mirams M . The skeleton: a multi-functional complex organ: the growth plate chondrocyte and endochondral ossification. J Endocrinol. 2011; 211(2):109-21. DOI: 10.1530/JOE-11-0048. View

14.

Oro A, Higgins K . Hair cycle regulation of Hedgehog signal reception. Dev Biol. 2003; 255(2):238-48. DOI: 10.1016/s0012-1606(02)00042-8. View

15.

Mak K, Kronenberg H, Chuang P, Mackem S, Yang Y . Indian hedgehog signals independently of PTHrP to promote chondrocyte hypertrophy. Development. 2008; 135(11):1947-56. PMC: 7188307. DOI: 10.1242/dev.018044. View

16.

Miao D, Liu H, Plut P, Niu M, Huo R, Goltzman D . Impaired endochondral bone development and osteopenia in Gli2-deficient mice. Exp Cell Res. 2004; 294(1):210-22. DOI: 10.1016/j.yexcr.2003.10.021. View

17.

Lakso M, Pichel J, Gorman J, Sauer B, Okamoto Y, Lee E . Efficient in vivo manipulation of mouse genomic sequences at the zygote stage. Proc Natl Acad Sci U S A. 1996; 93(12):5860-5. PMC: 39152. DOI: 10.1073/pnas.93.12.5860. View

18.

Joeng K, Long F . The Gli2 transcriptional activator is a crucial effector for Ihh signaling in osteoblast development and cartilage vascularization. Development. 2009; 136(24):4177-85. PMC: 2781053. DOI: 10.1242/dev.041624. View

19.

Wen X, Lai C, Evangelista M, Hongo J, de Sauvage F, Scales S . Kinetics of hedgehog-dependent full-length Gli3 accumulation in primary cilia and subsequent degradation. Mol Cell Biol. 2010; 30(8):1910-22. PMC: 2849461. DOI: 10.1128/MCB.01089-09. View

20.

Mau E, Whetstone H, Yu C, Hopyan S, Wunder J, Alman B . PTHrP regulates growth plate chondrocyte differentiation and proliferation in a Gli3 dependent manner utilizing hedgehog ligand dependent and independent mechanisms. Dev Biol. 2007; 305(1):28-39. DOI: 10.1016/j.ydbio.2007.01.031. View