Vangl2 participates in the primary ciliary assembly under low fluid shear stress in hUVECs

Sheng, Xin; Gao, Shuanglin; Sheng, Yan; Xie, Xiadan; Wang, Junhua; He, Yan

doi:10.1007/s00441-021-03546-0

Cited by 5 publications

(8 citation statements)

References 50 publications

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“…As a core PCP protein, VANGL2 is localized asymmetrically on the plasma membrane where it coordinates the orientation of cells within a tissue plane. Only more recently has VANGL2 been observed in membranous compartments within the cell, including the perinuclear space [4][5][6][7][8] , and, here, we show VANGL2 in the nucleus. A previous study in zebrafish also identified the NLS motif in the C-terminal region of VANGL2 30 .…”

Section: Discussionsupporting

confidence: 60%

Nuclear VANGL2 Inhibits Lactogenic Differentiation

Rubio,

Molinuevo,

Sanz-Gomez

et al. 2023

Preprint

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Planar cell polarity (PCP) proteins coordinate tissue morphogenesis by governing cell patterning and polarity. Asymmetrically localized on the plasma membrane of cells, PCP proteins are also trafficked by endocytosis, suggesting they may have intracellular functions that are dependent or independent of their extracellular role, but whether these functions extend to transcriptional control remains unknown. Here, we show the nuclear localization of transmembrane, PCP protein, VANGL2, in undifferentiated, but not differentiated, HC11 cells, which serve as a model for mammary lactogenic differentiation. Loss ofVangl2function results in upregulation of pathways related to STAT5 signaling. We identify DNA binding sites and a nuclear localization signal in VANGL2, and use CUT&RUN to demonstrate direct binding of VANGL2 to specific DNA binding motifs, including one in theStat5apromoter. Knockdown (KD) ofVangl2in HC11 cells and primary mammary organoids results in upregulation ofStat5a,Ccnd1andCsn2, larger acini and organoids, and precocious differentiation; phenotypes rescued by overexpression ofVangl2, but notVangl2ΔNLS. Together, these results advance a paradigm whereby PCP proteins coordinate tissue morphogenesis by keeping transcriptional programs governing differentiation in check.

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Section: Discussionsupporting

confidence: 60%

Nuclear VANGL2 Inhibits Lactogenic Differentiation

Rubio,

Molinuevo,

Sanz-Gomez

et al. 2023

Preprint

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“…The remaining 11 genes with well-defined ciliary function carrying high-impact variants (non-PTVs) encompassed: DNAH5 (motile cilia), 32 , 63 DNAI1 (motile cilia), 64 , 65 FLNA (ciliogenesis), 32 , 66 FUZ (ciliogenesis, primary and motile cilia), 67–69 LRP 6 (primary cilia), 70 , 71 MPDZ (ciliogenesis, motile cilia), 72 NOTCH2 (primary cilia), 73 , 74 PIK3R2 (primary cilia, ciliogenesis), 75 SMARCC1 (primary cilia), 76 , 77 TRIM71 (motile cilia) 78 and VANGL2 (primary and motile cilia, ciliogenesis). 32 , 52 , 79 In Table 2 , all the high-impact variant carrying genes with ciliary involvement are described and the genes with PTVs are underlined.…”

Section: Resultsmentioning

confidence: 99%

The genetic background of hydrocephalus in a population-based cohort: implication of ciliary involvement

Munch

Hedley

Hagen

et al. 2022

Brain Communications

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Hydrocephalus is one of the most common congenital disorders of the central nervous system and often displays psychiatric co-morbidities, in particular autism spectrum disorder. The disease mechanisms behind hydrocephalus are complex and not well understood, but some association with dysfunctional cilia in the brain ventricles and subarachnoid space has been indicated. A better understanding of the genetic aetiology of hydrocephalus, including the role of ciliopathies, may bring insights into a potentially shared genetic aetiology. In this population-based case-cohort study we, for the first time, investigated variants of postulated hydrocephalus candidate genes. Using this data, we aimed to investigate potential involvement of the ciliome in hydrocephalus and describe genotype-phenotype associations with autism spectrum disorder. One-hundred and twenty-one hydrocephalus candidate genes were screened in a whole-exome sequenced sub cohort of the Lundbeck Foundation Initiative for Integrative Psychiatric Research study, comprising 72 hydrocephalus patients and 4,181 background population controls. Candidate genes containing high-impact variants of interest were systematically evaluated for their involvement in ciliary function and autism spectrum disorder. The median age at diagnosis for the hydrocephalus patients was 0 years of age (range 0-27 years), the median age at analysis was 22 years (11-35 years), and 70.5 % were males. Median age for controls was 18 years (range 11-26 years) and 53.3 % were males. Fifty-two putative hydrocephalus-associated variants in 34 genes, were identified in 42 patients (58.3 %). In hydrocephalus cases, we found increased, but not significant, enrichment of high-impact protein altering variants (odds ratio 1.51, 95% CI 0.92-2.51, P = 0.096), which was driven by a significant enrichment of rare protein truncating variants (odds ratio 2.71, 95% CI 1.17-5.58, P = 0.011). Fourteen of the genes with high-impact variants are part of the ciliome, whereas another six genes affect cilia-dependent processes during neurogenesis. Furthermore, 15 of the 34 genes with high-impact variants and three of eight genes with protein truncating variants were associated with autism spectrum disorder. Because symptoms of other diseases may be neglected or masked by the hydrocephalus-associated symptoms, we suggest that patients with congenital hydrocephalus undergo clinical genetic assessment with respect to ciliopathies and autism spectrum disorder. Our results point to the significance of hydrocephalus as a ciliary disease in some cases. Future studies in brain ciliopathies may not only reveal new insights into hydrocephalus, but also, brain disease in the broadest sense, given the essential role of cilia for neurodevelopment.

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“…The remaining 11 genes with well-defined ciliary function carrying high-impact variants (non-PTV’s) encompassed: DNAH5 (motile cilia), 43, 58 DNAI1 (motile cilia), 59, 60 FLNA (ciliogenesis), 43, 61 FUZ (ciliogenesis, primary and motile cilia), 62-64 LRP6 (primary cilia), 65, 66 MPDZ (ciliogenesis, motile cilia), 67 NOTCH2 (primary cilia), 68,69 PIK3R2 (primary cilia, ciliogenesis), 70 SMARCC1 (primary cilia), 71,72 TRIM71 (motile cilia), 73 VANGL2 (primary and motile cilia, ciliogenesis) 43, 46, 74 In Table 3, all the high-impact variant carrying genes with ciliary involvement are described and the genes with PTV’s are underlined.…”

Section: Resultsmentioning

confidence: 99%

“…54 The neurofibromatosis changes may link to the function of primary cilia, as these are required for the formation of neural stem cells located in the subventricular zones, primarily of the lateral ventricles in adults and the third ventricle and optic pathway in children as well as for neurogenesis through Hedgehog signalling. [55][56][57] The remaining 11 genes with well-defined ciliary function carrying high-impact variants (non-PTV's) encompassed: DNAH5 (motile cilia), 43, 58 DNAI1 (motile cilia), 59,60 FLNA (ciliogenesis), 43,61 FUZ (ciliogenesis, primary and motile cilia), [62][63][64] LRP6 (primary cilia), 65,66 MPDZ (ciliogenesis, motile cilia), 67 NOTCH2 (primary cilia), 68,69 PIK3R2 (primary cilia, ciliogenesis), 70 SMARCC1 (primary cilia), 71,72 TRIM71(motile cilia), 73 VANGL2 (primary and motile cilia, ciliogenesis) 43,46,74 In Table 3, all the high-impact variant carrying genes with ciliary involvement are described and the genes with PTV's are underlined.…”

Section: Genes With Ciliary Functionmentioning

confidence: 99%

The genetic background of hydrocephalus in a population-based cohort: implication of ciliary involvement

Munch

Hedley

Hagen

et al. 2022

Preprint

View full text Add to dashboard Cite

Background Hydrocephalus is one of the most common congenital disorders of the central nervous system and often displays psychiatric co-morbidities, in particular autism spectrum disorder. The disease mechanisms behind hydrocephalus are complex and not well understood, but some association with dysfunctional cilia in the brain ventricles and subarachnoid space has been indicated. A better understanding of the genetic aetiology of hydrocephalus, including the role of ciliopathies, may bring insights into a potentially shared genetic aetiology. In this population-based case-cohort study we, for the first time, investigated variants of postulated hydrocephalus candidate genes. Using this data, we aimed to investigate potential involvement of the ciliome in hydrocephalus and describe genotype-phenotype associations with autism spectrum disorder, identified in the iPSYCH cohort. Methods One-hundred and twenty-one hydrocephalus candidate genes were screened in a whole-exome sequenced sub cohort of the iPSYCH study, comprising 72 hydrocephalus patients and 4,181 background population controls. Candidate genes containing high-impact variants of interest were systematically evaluated for their involvement in ciliary function and autism spectrum disorder. Results The median age at diagnosis for the hydrocephalus patients was 0 years of age (range 0-27 years), the median age at analysis was 22 years (11-35 years), and 70.5 % were males. Median age for controls was 18 years (range 11-26 years) and 53.3 % were males. Fifty-two putative hydrocephalus-associated variants in 34 genes, were identified in 42 patients (58.3 %). In hydrocephalus cases, we found increased, but not significant, enrichment of high-impact protein altering variants (OR 1.51, 95% CI 0.92-2.51, p = 0.096), which was driven by a significant enrichment of rare protein truncating variants (OR 2.71, 95% CI 1.17-5.58, p = 0.011). Fourteen of the genes with high-impact variants are part of the ciliome, whereas another six genes affect cilia-dependent processes during neurogenesis. Furthermore, 15 of the 34 genes with high-impact variants and three of eight genes with protein truncating variants were associated with autism spectrum disorder. Conclusions Because symptoms of other diseases may be neglected or masked by the hydrocephalus-associated symptoms and identification of co-morbidities may be of clinical significance, we suggest that patients with congenital hydrocephalus undergo clinical genetic assessment with respect to ciliopathies and autism spectrum disorder. Our results point to the significance of hydrocephalus as a ciliary disease in some cases. Future studies in brain ciliopathies may not only reveal new insights into hydrocephalus, but also, brain disease in the broadest sense, given the essential role of cilia for neurodevelopment.

show abstract

Vangl2 participates in the primary ciliary assembly under low fluid shear stress in hUVECs

Cited by 5 publications

References 50 publications

Nuclear VANGL2 Inhibits Lactogenic Differentiation

Nuclear VANGL2 Inhibits Lactogenic Differentiation

The genetic background of hydrocephalus in a population-based cohort: implication of ciliary involvement

The genetic background of hydrocephalus in a population-based cohort: implication of ciliary involvement

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