Signaling Pathways in Neurovascular Development

Rattner, Amir; Wang, Yanshu; Nathans, Jeremy

doi:10.1146/annurev-neuro-111020-102127

Cited by 16 publications

(7 citation statements)

References 141 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Based on the structure of APCDD1, the most attractive hypothesis for its action as a WNT inhibitor is that it binds directly to WNTs via their covalently linked PAM. To test this idea, we chose WNT7A from among the 19 mammalian WNTs, because WNT7A, like APCDD1, regulates CNS vascular development and barrier maturation ( 39 ). More specifically, WNT7A produced by glia and neurons activates FRIZZLED receptors on CNS endothelial cells, which respond with high-level WNT signaling, including high-level Apcdd1 expression.…”

Section: Resultsmentioning

confidence: 99%

Structure of WNT inhibitor adenomatosis polyposis coli down-regulated 1 (APCDD1), a cell-surface lipid-binding protein

Hsieh

Gabelli

Nathans

2023

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

Self Cite

View full text Add to dashboard Cite

Diverse extracellular proteins negatively regulate WNT signaling. One such regulator is adenomatosis polyposis coli down-regulated 1 (APCDD1), a conserved single-span transmembrane protein. In response to WNT signaling in a variety of tissues, APCDD1 transcripts are highly up-regulated. We have determined the three-dimensional structure of the extracellular domain of APCDD1, and this structure reveals an unusual architecture consisting of two closely apposed β-barrel domains (ABD1 and ABD2). ABD2, but not ABD1, has a large hydrophobic pocket that accommodates a bound lipid. The APCDD1 ECD can also bind to WNT7A, presumably via its covalently bound palmitoleate, a modification that is common to all WNTs and is essential for signaling. This work suggests that APCDD1 functions as a negative feedback regulator by titrating WNT ligands at the surface of responding cells.

show abstract

Section: Resultsmentioning

confidence: 99%

Structure of WNT inhibitor adenomatosis polyposis coli down-regulated 1 (APCDD1), a cell-surface lipid-binding protein

Hsieh

Gabelli

Nathans

2023

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…The Wnt/β-catenin pathway, an evolutionarily conserved signaling pathway [47], plays a critical role in LC [48] and participates in angiogenesis [49]. Cytoplasmic β-catenin is rapidly degraded by a large multiprotein complex termed the 'APC/Axin/GSK-3 complex', while nuclear β-catenin regulates the expression of Wnt target genes [50].…”

Section: Discussionmentioning

confidence: 99%

EPYC promotes laryngeal cancer carcinogenesis and angiogenesis via theWnt-Axin-β-catenin/VEGFR1 pathway

Zhou,

Liu,

et al. 2024

Preprint

View full text Add to dashboard Cite

Background EPYC is a member of a small family of leucine-rich repetitive proteoglycans (SLRPs) and contributes to the carcinogenesis of different cancers. However, the role of EPYC in laryngeal cancer (LC) is still unclear. This study aimed to determine the biological significance of EPYC in LC. Methods In public databases, EPYC was identified by screening as a hub angiogenesis-related differentially expressed gene (Ar-DEG), and this finding was validated in LC tissues. The biological role of EPYC as an LC promoter was verified by knocking down EPYC with small interfering RNA (siRNA) in LC cell lines. Gene set enrichment analysis (GSEA) of EPYC-related genes and verification experiments were subsequently conducted. The proangiogenic effect of EPYC and its specific mechanism were explored using a coculture model of HUVECs and LC cells. Results We found that EPYC was significantly upregulated in LC tissues vs. normal tissues, both in public databases and in in-house LC tissue samples, and was closely correlated with patient prognosis. EPYC knockdown in LC cells attenuated laryngeal carcinogenesis and angiogenesis, while the addition of rhEPYC partially restored tumor growth and neovascularization. GSEA revealed that genes upregulated in samples with high EPYC expression were enriched in the cell cycle. Mechanistically, EPYC may suppress the expression of Axin, a β-catenin degradation complex protein that activates Wnt/β-catenin, or promote the degradation of VEGFR1 and reduce its ability to act as a decoy of VEGF to increase VEGF secretion and promote angiogenesis. Conclusion We showed that EPYC is overexpressed in LC and promotes LC carcinogenesis and angiogenesis via the Wnt-Axin-β-catenin/VEGFR1-VEGF pathway, suggesting EPYC as a novel therapeutic target for LC.

show abstract

“…These precedents in other cell types suggest that reduced LEF1 -and presumably reduced canonical WNT signaling -in ECs in the infected arachnoid could reflect BETA-CATENIN downregulation via the activated NF kappaB pathway. Reduced canonical WNT signaling in ECs would be predicted to reduce BBB integrity (Rattner at al., 2022).…”

Section: Discussionmentioning

confidence: 99%

Bacterial meningitis in the early postnatal mouse studied at single-cell resolution

Wang

Rattner

Nathans

2023

Preprint

Self Cite

View full text Add to dashboard Cite

Bacterial meningitis is a major cause of morbidity and mortality, especially among infants and the elderly. Here we study mice to assess the response of each of the major meningeal cell types to early postnatal E. coli infection using single nucleus RNA sequencing (snRNAseq), immunostaining, and genetic and pharamacologic perturbations of immune cells and immune signaling. Flat mounts of the dissected arachnoid and dura were used to facilitate high-quality confocal imaging and quantification of cell abundances and morphologies. Upon infection, the major meningeal cell types, including endothelial cells (ECs), macrophages, and fibroblasts, exhibit distinctive changes in their transcriptomes. Additionally, ECs in the arachnoid redistribute CLDN5 and PECAM1, and arachnoid capillaries exhibit foci with reduced blood-brain barrier integrity. The vascular response to infection appears to be largely driven by TLR4 signaling, as determined by the nearly identical response induced by LPS administration and by the blunted response to infection in Tlr4 knockout mice.

show abstract

Signaling Pathways in Neurovascular Development

Cited by 16 publications

References 141 publications

Structure of WNT inhibitor adenomatosis polyposis coli down-regulated 1 (APCDD1), a cell-surface lipid-binding protein

Structure of WNT inhibitor adenomatosis polyposis coli down-regulated 1 (APCDD1), a cell-surface lipid-binding protein

EPYC promotes laryngeal cancer carcinogenesis and angiogenesis via theWnt-Axin-β-catenin/VEGFR1 pathway

Bacterial meningitis in the early postnatal mouse studied at single-cell resolution

Contact Info

Product

Resources

About