Stabilization of Speckle-type POZ Protein (Spop) by Daz Interacting Protein 1 (Dzip1) Is Essential for Gli Turnover and the Proper Output of Hedgehog Signaling

Schwend, Tyler; Jin, Zhigang; Jiang, Kai; Mitchell, Brian J.; Jia, Jianhang; Yang, Jing

doi:10.1074/jbc.m113.512962

Cited by 17 publications

(19 citation statements)

References 63 publications

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“…Recent studies using cultured mammalian cells or mRNA injection in Xenopus eggs also suggested a negative role of Spop in Hh signaling (18)(19)(20)(21)24). It is worth noting that a key difference between these studies and our in vivo data lies in the roles of Spop in the regulation of Gli2, the primary activator of the mammalian Hh pathway.…”

Section: Discussioncontrasting

confidence: 51%

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Spop promotes skeletal development and homeostasis by positively regulating Ihh signaling

Cai

Liu

2016

Proc. Natl. Acad. Sci. U.S.A.

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Indian Hedgehog (Ihh) regulates chondrocyte and osteoblast differentiation through the Glioma-associated oncogene homolog (Gli) transcription factors. Previous in vitro studies suggested that Speckletype 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.T he human skeleton provides essential mechanical support, mobility, and mineral storage critical for health (1). In development, most bones form through endochondral ossification in which chondrocytes in the growth plate proliferate, undergo hypertrophic differentiation, and secrete calcium-containing extracellular matrix (2). The osteoblasts in the perichondrium, a thin layer of tissue surrounding the cartilage, replace the dying chondrocytes and secrete more bone matrix. On the other hand, osteoclasts, derived from white blood cells, invade and digest bone matrix. The balance between the osteoblast and osteoclast activities allows calcium homeostatic control and bone health. In osteopenia and osteoporosis, conditions afflicting more than 10 million Americans, an abnormal decrease in osteoblast activity or increase in osteoclast activity results in the loss of bone mass (1, 3). Unfortunately, our understanding of these bone diseases has been hindered by incomplete knowledge in the molecular mechanisms underlying endochondral bone development and remodeling.Indian Hedgehog (Ihh), a member of the Hedgehog (Hh) family of signaling proteins, is essential for endochondral bone development (4). Ihh regulates gene expression through the Gli family of transcription factors, which act as both transcriptional activators and repressors (5). In the absence of Hh, efficient proteolytic processing turns Gli3 into a transcriptional repressor (Gli3R) whereas processing of Gli2 is rather inefficient (6-8). Hh inhibits Gli processing and converts the full-length Gli proteins into transcriptional activators. Both Gli2 and Gli3 play important roles in the regulation of bone formation downstream of Ihh (9-12).Ihh maintains the expression of parathyroid hormone-like peptide (Pthlh) (Mouse Genome Informatics) in the periarticular perichondrium (13), which then stimulates the prol...

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Section: Discussioncontrasting

confidence: 51%

“…The Spop homolog in Drosophila, known as hib or rdx, also mediates the degradation of Ci, the sole Gli family member in flies, and inhibits Hh signaling (22,23). Overexpression of Spop in Xenopus similarly reduces Hh pathway activation (24). An Spop mutant mouse strain was analyzed previously, but defects only in endocrine pancreas were reported (25).…”

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confidence: 99%

Spop promotes skeletal development and homeostasis by positively regulating Ihh signaling

Cai

Liu

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Interestingly, 73% of injected embryos had bodies that were bent toward the injected side, which was likely to be due to a shortened A/P axis on the injected side. Coinjection of Gli1 morpholino (Nguyen et al, 2005;Schwend et al, 2013) clearly rescued the Rusc1 knockdown phenotypes, with the majority of embryos (96%, n=45) developing a straight body axis and only 16% of embryos showing mildly affected eyes (Fig. 8F).…”

Section: Rusc1 Inhibits Hh Signaling During Xenopus Embryonic Developmentioning

confidence: 99%

“…To determine if Rusc1 inhibits Hh signaling during development, we took advantage of the animal cap assay, which is an in vitro assay for studying Hh signaling in Xenopus embryonic tissues (Rorick et al, 2007;Min et al, 2011;Schwend et al, 2013). In Chordin (Chd) neuralized animal caps, injection of R1-MO caused a 2-fold increase in the expression of gli1, ptc2 and hhip at stage 22 and a modest increase in the expression of ptc1 (Fig.…”

Section: Rusc1 Inhibits Hh Signaling During Xenopus Embryonic Developmentioning

confidence: 99%

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Members of the Rusc protein family interact with Sufu and inhibit vertebrate Hedgehog signaling

Jin¹,

Schwend²,

Fu³

et al. 2016

Journal of Cell Science

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Hedgehog (Hh) signaling is fundamentally important for development and adult tissue homeostasis. It is well established that in vertebrates Sufu directly binds and inhibits Gli proteins, the downstream mediators of Hh signaling. However, it is unclear how the inhibitory function of Sufu towards Gli is regulated. Here we report that the Rusc family of proteins, the biological functions of which are poorly understood, form a heterotrimeric complex with Sufu and Gli. Upon Hh signaling, Rusc is displaced from this complex, followed by dissociation of Gli from Sufu. In mammalian fibroblast cells, knockdown of Rusc2 potentiates Hh signaling by accelerating signaling-induced dissociation of the Sufu-Gli protein complexes. In Xenopus embryos, knockdown of Rusc1 or overexpression of a dominant-negative Rusc enhances Hh signaling during eye development, leading to severe eye defects. Our study thus uncovers a novel regulatory mechanism controlling the response of cells to Hh signaling in vertebrates.

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Comparative analysis of genes regulated by Dzip1/iguana and hedgehog in zebrafish

Arnold

Lamont

Walker

et al. 2015

Developmental Dynamics

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Background: The zebrafish genetic mutant iguana (igu) has defects in the ciliary basal body protein Dzip1, causing improper cilia formation. Dzip1 also interacts with the downstream transcriptional activators of Hedgehog (Hh), the Gli proteins, and Hh signaling is disrupted in igu mutants. Hh governs a wide range of developmental processes, including stabilizing developing blood vessels to prevent hemorrhage. Using igu mutant embryos and embryos treated with the Hh pathway antagonist cyclopamine, we conducted a microarray to determine genes involved in Hh signaling mediating vascular stability. Results: We identified 40 genes with significantly altered expression in both igu mutants and cyclopamine-treated embryos. For a subset of these, we used in situ hybridization to determine localization during embryonic development and confirm the expression changes seen on the array. Conclusions: Through comparing gene expression changes in a genetic model of vascular instability with a chemical inhibition of Hh signaling, we identified a set of 40 differentially expressed genes with potential roles in vascular stabilization. Developmental Dynamics 244:211-223, 2015. V C 2014 Wiley Periodicals, Inc.

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Stabilization of Speckle-type POZ Protein (Spop) by Daz Interacting Protein 1 (Dzip1) Is Essential for Gli Turnover and the Proper Output of Hedgehog Signaling

Cited by 17 publications

References 63 publications

Spop promotes skeletal development and homeostasis by positively regulating Ihh signaling

Spop promotes skeletal development and homeostasis by positively regulating Ihh signaling

Members of the Rusc protein family interact with Sufu and inhibit vertebrate Hedgehog signaling

Comparative analysis of genes regulated by Dzip1/iguana and hedgehog in zebrafish

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