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

2021 ◽  
Vol 9 ◽  
Author(s):  
Zhi-Jie Xia ◽  
Xin-Xin I. Zeng ◽  
Mitali Tambe ◽  
Bobby G. Ng ◽  
P. Duc S. Dong ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Body Length ◽  
Bone Development ◽  
Heterozygous Mutation ◽  
Zebrafish Embryos ◽  
Convergent Extension ◽  
Canonical Wnt Signaling ◽  
Developmental Defects ◽  
Primordial Dwarfism ◽  
Canonical Wnt

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.

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

2021 ◽  
Author(s):  
Zhi-Jie Xia ◽  
Xin-Xin I. Zeng ◽  
Mitali Tambe ◽  
Bobby G. Ng ◽  
Duc Si Dong ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Body Length ◽  
Bone Development ◽  
Heterozygous Mutation ◽  
Convergent Extension ◽  
Canonical Wnt Signaling ◽  
Developmental Defects ◽  
Larval Stages ◽  
Cog Complex ◽  
Canonical Wnt

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.

scholarly journals Crip2 has dual functions in the cytoplasm and nucleus, induces non-canonical Wnt signaling during convergent extension movement in zebrafish notochord

2007 ◽  
Vol 306 (1) ◽  
pp. 437
Author(s):  
Yasuyuki S. Kida ◽  
Takayuki Sato ◽  
Asami Suto ◽  
Kouta Y. Miyasaka ◽  
Mari Minami ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Convergent Extension ◽  
Canonical Wnt Signaling ◽  
Canonical Wnt ◽  
Dual Functions

scholarly journals Conformational change of Dishevelled plays a key regulatory role in the Wnt signaling pathways

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Ho-Jin Lee ◽  
De-Li Shi ◽  
Jie J Zheng
Keyword(s):  
Wnt Signaling ◽  
Conformational Change ◽  
Intracellular Signaling ◽  
Pdz Domain ◽  
Wnt Signaling Pathway ◽  
Binding Pocket ◽  
Convergent Extension ◽  
Canonical Wnt Signaling ◽  
Closed Conformation ◽  
Canonical Wnt

The intracellular signaling molecule Dishevelled (Dvl) mediates canonical and non-canonical Wnt signaling via its PDZ domain. Different pathways diverge at this point by a mechanism that remains unclear. Here we show that the peptide-binding pocket of the Dvl PDZ domain can be occupied by Dvl's own highly conserved C-terminus, inducing a closed conformation. In Xenopus, Wnt-regulated convergent extension (CE) is readily affected by Dvl mutants unable to form the closed conformation than by wild-type Dvl. We also demonstrate that while Dvl cooperates with other Wnt pathway elements to activate canonical Wnt signaling, the open conformation of Dvl more effectively activates Jun N-terminal kinase (JNK). These results suggest that together with other players in the Wnt signaling pathway, the conformational change of Dvl regulates Wnt stimulated JNK activity in the non-canonical Wnt signaling.

scholarly journals Alternative isoforms of KDM2A and KDM2B lysine demethylases negatively regulate canonical Wnt signaling

2020 ◽  
Author(s):  
Dijana Lađinović ◽  
Daniel Pinkas ◽  
Otakar Raška ◽  
František Liška ◽  
Ivan Raška ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Transcriptional Repression ◽  
Target Genes ◽  
Luciferase Reporter ◽  
Dna Binding Domain ◽  
Biological Processes ◽  
Canonical Wnt Signaling ◽  
Developmental Defects ◽  
Canonical Wnt ◽  
Alternative Isoforms

AbstractA precisely balanced activity of canonical Wnt signaling is essential for a number of biological processes and its perturbation leads to developmental defects or diseases. Here, we demonstrate that alternative isoforms of the KDM2A and KDM2B lysine demethylases have the ability to negatively regulate canonical Wnt signaling. These KDM2A and KDM2B isoforms (KDM2A-SF and KDM2B-SF) lack the N-terminal demethylase domain, but they are able to bind to activated promoters in order to repress them. We have observed that KDM2A-SF and KDM2B-SF bind to and repress the promoters of AXIN2 and CYCLIN D1, two canonical Wnt signaling target genes. Moreover, KDM2A-SF and KDM2B-SF can repress a Wnt-responsive luciferase reporter. The transcriptional repression mediated by KDM2A-SF and KDM2B-SF, but also by KDM2A-LF, is dependent on their DNA binding domain, while the N-terminal demethylase domain is dispensable for this process. Surprisingly, KDM2B-LF is unable to repress both the endogenous promoters and the luciferase reporter. Finally, we show that both KDM2A-SF and KDM2B-SF are able to interact with TCF7L1, one of the transcriptional mediators of canonical Wnt signaling. KDM2A-SF and KDM2B-SF are thus likely to affect the transcription of the TCF7L1 target genes also through this interaction.

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