The Hippo pathway component Wwc2 is a key regulator of embryonic development and angiogenesis in mice

Hermann, Anke; Wu, Guangming; Nedvetsky, Pavel I.; Brücher, Viktoria Constanze; Egbring, Charlotte; Bonse, Jakob; Höffken, Verena; Wennmann, Dirk Oliver; Marks, Matthias; Krahn, Michael P.; Schöler, Hans R.; Heiduschka, Peter; Pavenstädt, Hermann; Kremerskothen, Joachim

doi:10.1038/s41419-021-03409-0

Cited by 18 publications

(15 citation statements)

References 71 publications

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“…In contrast, WWC1 is primary expressed in epithelial cells. Moreover, recent studies showed that a WWC2 deletion results in severe defects in angiogenesis [ 34 ]. These data confirm our findings about WWC1 playing a subordinate role in angiogenesis, as it is of secondary importance for the most essential cell type of blood vessels, the ECs.…”

Section: Discussionmentioning

confidence: 99%

“…Equally unknown is whether there is a tissue-specific difference in composition of Hippo signalling pathway. Recently, we have demonstrated that WWC2 protein plays an important role during embryonic and postnatal angiogenesis [ 34 ]. In this study, we analysed whether WWC2 is only important for retinal angiogenesis during development or also required for vascular maintenance.…”

Section: Introductionmentioning

confidence: 99%

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Lack of WWC2 Protein Leads to Aberrant Angiogenesis in Postnatal Mice

Brücher

Egbring

Plagemann

et al. 2021

IJMS

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The WWC protein family is an upstream regulator of the Hippo signalling pathway that is involved in many cellular processes. We examined the effect of an endothelium-specific WWC1 and/or WWC2 knock-out on ocular angiogenesis. Knock-outs were induced in C57BL/6 mice at the age of one day (P1) and evaluated at P6 (postnatal mice) or induced at the age of five weeks and evaluated at three months of age (adult mice). We analysed morphology of retinal vasculature in retinal flat mounts. In addition, in vivo imaging and functional testing by electroretinography were performed in adult mice. Adult WWC1/2 double knock-out mice differed neither functionally nor morphologically from the control group. In contrast, the retinas of the postnatal WWC knock-out mice showed a hyperproliferative phenotype with significantly enlarged areas of sprouting angiogenesis and a higher number of tip cells. The branching and end points in the peripheral plexus were significantly increased compared to the control group. The deletion of the WWC2 gene was decisive for these effects; while knocking out WWC1 showed no significant differences. The results hint strongly that WWC2 is an essential regulator of ocular angiogenesis in mice. As an activator of the Hippo signalling pathway, it prevents excessive proliferation during physiological angiogenesis. In adult animals, WWC proteins do not seem to be important for the maintenance of the mature vascular plexus.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lack of WWC2 Protein Leads to Aberrant Angiogenesis in Postnatal Mice

Brücher

Egbring

Plagemann

et al. 2021

IJMS

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“…Functional studies of the WWC2 gene can be performed by immunohistochemical analysis or western blot using antibodies against the WWC2 protein. WWC2 mRNA expression studies can be performed by various methods such as whole-mount in situ hybridization or quantitative reverse transcriptase polymerase chain reaction ( 34 , 35 ). In this study, we did not perform a functional study of the WWC2 gene since we did not have lung tissue samples obtained from deceased patients with PPHN and a mouse model with PPHN could not be created in our setting.…”

Section: Discussionmentioning

confidence: 99%

“…Length of hospital stay (days)22(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34) In-hospital mortality2 (3.7) Data are presented as mean ± standard deviation, median (interquartile range), or n (%). PPHN, persistent pulmonary hypertension of the newborn.…”

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confidence: 99%

Genome-wide association study identifies WWC2 as a possible locus associated with persistent pulmonary hypertension of the newborn in the Thai population

Nakwan¹,

Kunhapan²,

Chaiyasung³

et al. 2023

Transl Pediatr

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Background There is known to be significant genetic involvement in persistent pulmonary hypertension of the newborn (PPHN), but to date there is not a clear understanding of this situation, and clarifying that involvement would be of considerable assistance in devising effective treatments for the disease. This case-control study was undertaken to search for genetic variants associated with PPHN in the Thai population using a genome-wide association study (GWAS). Methods A 659,184 single nucleotide polymorphisms from 387 participants (54 PPHN cases and 333 healthy participants) were genotyped across the human genome using an Illumina Asian Screening Array-24 v1.0 BeadChip Array. After quality control, we obtained 443,063 autosomal SNPs for the GWAS analysis. The FaST-LMM and R packages were used for all statistical analyses. Results For the case-control analysis, the genomic inflation factor (λ) was 1.016, rs149768622 T>C in the first intron of WWC2 gene showed the strongest association with a P value of 3.76E-08 and odds ratio (OR) of 13.24 (95% CI: 3.91–44.78). The variants at the LOC102723906 / LOC105377599 , CADM4 , GPM6A , CIT , RIMBP2 , LOC105374510 , LOC105375193 , PTPRN2 , CDK14 , and LCORL loci showed suggestive evidence of associations with PPHN (P<1E-05). Conclusions This GWAS found that rs149768622 T>C in the WWC2 gene was possibly associated with PPHN. However, replication and functional studies are needed to validate this association and further explore the role(s) of the WWC2 gene in PPHN.

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“…Cell lysate preparation and Western blotting analysis were performed as described earlier. 14 Briefly, confluent-grown cells from a 10 cm diameter plate or 15 mg snap-frozen human adult testicular tissue with CS (n = 1) were lysed using 500 μL IP buffer (1% Triton X-100, 20 mM Tris-HCl pH 7.4, 20 mM NaCl, 50 mM NaF, 15 mM Na 4 P 2 O 7 , 1 mM EDTA) containing phosphatase and protease inhibitor cocktails (P5726-5ML, P0044-5ML, P8340-1ML; Sigma Aldrich; 04693116001; Roche, Basel, Switzerland). Cells were scraped with a cell scraper and tissue was sheared with a small mortar.…”

Section: Western Blot Analysis Of Wwc2 In Cell and Tissue Lysatesmentioning

confidence: 99%

WWC2 expression in the testis: Implications for spermatogenesis and male fertility

et al. 2023

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The family of WWC proteins is known to regulate cell proliferation and organ growth control via the Hippo signaling pathway. As WWC proteins share a similar domain structure and a common set of interacting proteins, they are supposed to fulfill compensatory functions in cells and tissues. While all three WWC family members WWC1, WWC2, and WWC3 are found co-expressed in most human organs including lung, brain, kidney, and liver, in the testis only WWC2 displays a relatively high expression. In this study, we investigated the testicular WWC2 expression in spermatogenesis and male fertility. We show that the Wwc2 mRNA expression level in mouse testes is increased during development in parallel with germ cell proliferation and differentiation. The cellular expression of each individual WWC family member was evaluated in published single-cell mRNA datasets of murine and human testes demonstrating a high WWC2 expression predominantly in early spermatocytes. In line with this, immunohistochemistry revealed cytosolic WWC2 protein expression in primary spermatocytes from human testes displaying full spermatogenesis. In accordance with these findings, markedly lower WWC2 expression levels were detected in testicular tissues from mice and men lacking germ cells. Finally, analysis of whole-exome sequencing data of male patients affected by infertility and unexplained severe spermatogenic failure revealed several heterozygous, rare WWC2 gene variants with a

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The Hippo pathway component Wwc2 is a key regulator of embryonic development and angiogenesis in mice

Cited by 18 publications

References 71 publications

Lack of WWC2 Protein Leads to Aberrant Angiogenesis in Postnatal Mice

Lack of WWC2 Protein Leads to Aberrant Angiogenesis in Postnatal Mice

Genome-wide association study identifies WWC2 as a possible locus associated with persistent pulmonary hypertension of the newborn in the Thai population

WWC2 expression in the testis: Implications for spermatogenesis and male fertility

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