CRELD2 Is a Novel LRP1 Chaperone That Regulates Noncanonical WNT Signaling in Skeletal Development

Dennis, Ella P.; Edwards, Sarah; Jackson, Robert M.; Hartley, Claire; Tsompani, Dimitra; Capulli, Mattia; Teti, Anna; Boot-Handford, RP; Young, David A.; Piróg, Katarzyna A.; Briggs, Michael D.

doi:10.1002/jbmr.4010

Cited by 14 publications

(14 citation statements)

References 53 publications

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“…Misexpression of Zwnt4 (zebrafish wnt4) and Xwnt4 (Xenopus wnt4) in zebrafish causes shortened trunk and tail (26) and abnormal chondrocyte intercalation in Meckel's cartilage (our data), confirming Wnt4 is involved in regulation of chondrocyte behavior, like gpc4 and wnt5b (25). In mice, Wnt4 defects led to short-limb dwarfism (43). Most relevant, conditional expression of Wnt4 in mice also causes dwarfism with small skeletons, dome-shaped skull and small jaws (44).…”

Section: Discussionsupporting

confidence: 68%

A single heterozygous mutation in COG4 disrupts zebrafish early development via Wnt signaling

Xia

Zeng

Tambe

et al. 2021

Preprint

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Saul-Wilson syndrome (SWS) is a rare, skeletal dysplasia with progeroid appearance and primordial dwarfism. It is caused by a heterozygous, dominant variant (p.G516R) in COG4, a subunit of the Conserved Oligomeric Golgi (COG) complex involved in intracellular vesicular transport. Our previous work has shown the intracellular disturbances caused by this mutation; however, the pathological mechanism of SWS needs further investigation. We sought to understand the molecular mechanism of specific aspects of the SWS phenotype by analyzing SWS-derived fibroblasts and zebrafish embryos expressing this dominant variant. SWS fibroblasts accumulate glypicans, a group of heparan sulfate proteoglycans (HSPGs) critical for growth and bone development through multiple signaling pathways. Consistently, we find that glypicans are increased in embryos expressing the COG4p.G516R variant. These animals show phenotypes consistent with convergent extension (CE) defects during gastrulation, shortened body length, and malformed jaw cartilage chondrocyte intercalation at larval stages. Since non-canonical Wnt signaling was shown in zebrafish to be related to the regulation of these processes by Glypican 4, we assessed wnt levels and found a selective increase of wnt4 transcripts in the presence of COG4p.G516R. Moreover, overexpression of wnt4 mRNA phenocopies these developmental defects. LGK974, an inhibitor of Wnt signaling corrects the shortened body length at low concentrations but amplifies it at slightly higher concentrations. WNT4 and the non-canonical Wnt signaling component phospho-JNK are also elevated in cultured SWS-derived fibroblasts. Similar results from SWS cell lines and zebrafish point to altered non-canonical Wnt signaling as one possible mechanism underlying SWS pathology.

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Section: Discussionsupporting

confidence: 68%

A single heterozygous mutation in COG4 disrupts zebrafish early development via Wnt signaling

Xia

Zeng

Tambe

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…data), confirming Wnt4 is involved in regulation of chondrocyte behavior, like gpc4 and wnt5b (Sisson et al, 2015). In mice, Wnt4 defects led to short-limb dwarfism (Dennis et al, 2020).…”

Section: Discussionmentioning

confidence: 55%

“…Besides increased glypicans, it is interesting that we also found an elevated wnt4 transcript in SWS-derived cells and COG4 p .G516R -injected zebrafish embryos. Studies have shown that the cell surface receptor could directly regulate WNT4 expression in chondrocytes ( Dennis et al, 2020 ). Therefore, we hypothesize that the increased WNT4 is probably a compensatory transcriptional response to increased glypicans.…”

Section: Discussionmentioning

confidence: 99%

A Dominant Heterozygous Mutation in COG4 Causes Saul–Wilson Syndrome, a Primordial Dwarfism, and Disrupts Zebrafish Development via Wnt Signaling

Xia

Zeng

Tambe

et al. 2021

Front. Cell Dev. Biol.

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Saul–Wilson syndrome (SWS) is a rare, skeletal dysplasia with progeroid appearance and primordial dwarfism. It is caused by a heterozygous, dominant variant (p.G516R) in COG4, a subunit of the conserved oligomeric Golgi (COG) complex involved in intracellular vesicular transport. Our previous work has shown the intracellular disturbances caused by this mutation; however, the pathological mechanism of SWS needs further investigation. We sought to understand the molecular mechanism of specific aspects of the SWS phenotype by analyzing SWS-derived fibroblasts and zebrafish embryos expressing this dominant variant. SWS fibroblasts accumulate glypicans, a group of heparan sulfate proteoglycans (HSPGs) critical for growth and bone development through multiple signaling pathways. Consistently, we find that glypicans are increased in zebrafish embryos expressing the COG4p.G516R variant. These animals show phenotypes consistent with convergent extension (CE) defects during gastrulation, shortened body length, and malformed jaw cartilage chondrocyte intercalation at larval stages. Since non-canonical Wnt signaling was shown in zebrafish to be related to the regulation of these processes by glypican 4, we assessed wnt levels and found a selective increase of wnt4 transcripts in the presence of COG4p.G516R. Moreover, overexpression of wnt4 mRNA phenocopies these developmental defects. LGK974, an inhibitor of Wnt signaling, corrects the shortened body length at low concentrations but amplifies it at slightly higher concentrations. WNT4 and the non-canonical Wnt signaling component phospho-JNK are also elevated in cultured SWS-derived fibroblasts. Similar results from SWS cell lines and zebrafish point to altered non-canonical Wnt signaling as one possible mechanism underlying SWS pathology.

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“…Tibiae from female mice aged 7 months were dissected, fixed in 4% formaldehyde for 24 h and embedded in methyl methacrylate without decalcification. 5 μm sections were taken for bone histomorphometry, performed as detailed previously 46 . In brief, sections were stained with Von Kossa stain to analyse bone mineralisation, 1% Toluidine blue to analyse osteoblast number, and stained for tartrate-resistant acid phosphatase (TRAcP) to analyse osteoclast number and surface area.…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial dysfunction impairs osteogenesis, increases osteoclast activity, and accelerates age related bone loss

Dobson

Dennis

Hipps

et al. 2020

Sci Rep

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The pathogenesis of declining bone mineral density, a universal feature of ageing, is not fully understood. Somatic mitochondrial DNA (mtDNA) mutations accumulate with age in human tissues and mounting evidence suggests that they may be integral to the ageing process. To explore the potential effects of mtDNA mutations on bone biology, we compared bone microarchitecture and turnover in an ageing series of wild type mice with that of the PolgA mut/mut mitochondrial DNA ‘mutator’ mouse. In vivo analyses showed an age-related loss of bone in both groups of mice; however, it was significantly accelerated in the PolgA mut/mut mice. This accelerated rate of bone loss is associated with significantly reduced bone formation rate, reduced osteoblast population densities, increased osteoclast population densities, and mitochondrial respiratory chain deficiency in osteoblasts and osteoclasts in PolgA mut/mut mice compared with wild-type mice. In vitro assays demonstrated severely impaired mineralised matrix formation and increased osteoclast resorption by PolgA mut/mut cells. Finally, application of an exercise intervention to a subset of PolgA mut/mut mice showed no effect on bone mass or mineralised matrix formation in vitro. Our data demonstrate that mitochondrial dysfunction, a universal feature of human ageing, impairs osteogenesis and is associated with accelerated bone loss.

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CRELD2 Is a Novel LRP1 Chaperone That Regulates Noncanonical WNT Signaling in Skeletal Development

Cited by 14 publications

References 53 publications

A single heterozygous mutation in COG4 disrupts zebrafish early development via Wnt signaling

A single heterozygous mutation in COG4 disrupts zebrafish early development via Wnt signaling

A Dominant Heterozygous Mutation in COG4 Causes Saul–Wilson Syndrome, a Primordial Dwarfism, and Disrupts Zebrafish Development via Wnt Signaling

Mitochondrial dysfunction impairs osteogenesis, increases osteoclast activity, and accelerates age related bone loss

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