Depletion of VGLL4 Causes Perinatal Lethality without Affecting Myocardial Development

Sheldon, Caroline; Farley, Aaron; Ma, Qing; Pu, William T.; Lin, Zhiqiang

doi:10.3390/cells11182832

Cited by 6 publications

(6 citation statements)

References 39 publications

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“…Few functional validation studies with genetically engineered mouse models (GEMM) for homozygous deletion of VGLL4 as a driver have been conducted (Cai et al, 2022). Indeed GEMM studies have mostly focused on the role of VGLL4 in development (Sheldon et al, 2022) rather than cancer. It is only very recently because of the recognition of VGLL4’s importance as a negative regulator of the YAP/TEAD oncogenic transcriptional complex ( Figure 12 ) that dedicated GEMM studies with cancer have been undertaken.…”

Section: Resultsmentioning

confidence: 99%

The puzzling case of the 3p25 homozygous deletion: the target is notVHLbutVGLL4andATG7

Muller,

Behr

2023

Preprint

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The 3p25 locus experiences recurrent homozygous deletions in diverse carcinomas. A validated tumor suppressor gene (TSG),VHLhas long been assumed to be the target of this deletion.Here, we show that homozygous deletions at the 3p25 locus are common in renal clear cell carcinoma (RCC) and squamous cell carcinomas but that these do not center onVHLbut on two nearby overlapping genes,VGLL4andATG7. While hypomorphic mutations ofVHLcoupled with heterozygous deletions are undoubtedly a driver in RCC, DepMap CRISPR data indicate that the complete absence ofVHLis broadly detrimental to cancer cells. Re-examination of TCGA and PDX data calls into question whetherVHLis ever homozygous deleted, even in RCC.Instead, multiple lines of evidence support the homozygous deletion ofVGLL4as a driver event in squamous cell carcinomas and the homozygous deletion ofATG7as a driver in RCC, with important implication for precision oncology. VGLL4 is the major negative regulator of the YAP/TEAD complex, with elimination of VGLL4 leading to hyperactive oncogenic YAP-dependent transcriptional activity which could be targeted by clinically emerging YAP/TEAD inhibitors. ATG7 is a critical regulator of autophagy, limiting proliferation in conditions of nutrient limitation and its deletion may open novel vulnerabilities for synthetic lethality.

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Section: Resultsmentioning

confidence: 99%

The puzzling case of the 3p25 homozygous deletion: the target is notVHLbutVGLL4andATG7

Muller,

Behr

2023

Preprint

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“…We previously showed that activation of VGLL4 decreased TEAD1 protein level in the heart (Lin et al, 2016) and knocking out VGLL4 increased TEAD1 (Sheldon et al, 2022). We then checked whether inactivation of VGLL4 affected TEAD1 protein expression in BAT.…”

Section: Deletion Of Vgll4 Activates Igf-akt Pathwaymentioning

confidence: 98%

“…We have previously reported that whole-body depletion of VGLL4 led to perinatal death (Sheldon et al, 2022). While characterizing the phenotype of the Vgll4 knockout (Vko) pups, we noticed that the Vko newborn pups had consistent dents in the interscapular regions, which led us to examine the interscapular BAT depot.…”

Section: Mutating Vgll4 Causes Bat Paucitymentioning

confidence: 98%

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Vestigial like 4 regulates the adipogenesis of classical brown adipose tissue

Zhou,

Kessinger,

et al. 2024

Preprint

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Brown adipose tissue (BAT) is mammals’ primary non-shivering thermogenesis organ, and the molecular mechanisms regulating BAT growth and adipogenesis are largely unknown. The Hippo-YAP pathway has been well-known for controlling organ size, and Vestigial like 4 (VGLL4) is a transcriptional regulator that modulates the Hippo-YAP pathway by competing against YAP for binding to TEAD proteins. In this study, we dissected the function of VGLL4 in regulating BAT development. We generated a conventionalVgll4mutant mouse line, in which the two Tondu (TDU) domains of VGLL4 were disrupted. We found that deletion of the TDU domains of VGLL4 resulted in perinatal lethality and paucity of the interscapular BAT. Histological and magnetic resonance imaging studies confirmed that the adipogenesis of BAT was impaired inVgll4mutants. Adeno-associated virus (AAV) mediated, brown adipocyte-specific overexpression of VGLL4 increased BAT volume and protected the adult male mice from acute cold stress. Genomic studies suggest that VGLL4/TEAD1 complex directly regulates the myogenic and adipogenic gene expression programs of BAT. In conclusion, our data identify VGLL4 as a previously unrecognized adipogenesis factor that regulates classical BAT development.

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“…In Xenopus and zebrafish the transcripts of the different vgll4 paralogs show a dynamic developmental expression pattern in different tissues ( Faucheux et al, 2010 ; Barrionuevo et al, 2014 ; Xue et al, 2018 ) and in zebrafish the mRNA of two ( Xue et al, 2018 ) ( vgll4a ; vgll4b ) of the three paralogs ( vgll4a , vgll4b and vgll4l ) have been detected at the 1 cell stage ( Xue et al, 2018 ), suggesting a possible early function. Although there are additional and species-specific phenotypes that involve later developing organs ( Fillatre et al, 2019 ; Xue et al, 2019 ; Wang et al, 2020 ), loss of function studies in mice and analysis of genetic variants in the teleost Scatophagus argus suggest that Vgll4 participates in the regulation of body size ( Feng et al, 2019 ; Suo et al, 2020 ; Yang et al, 2020 ; Sheldon et al, 2022 ), a trait that is often altered as the consequence of an abnormal gastrulation.…”

Section: Introductionmentioning

confidence: 99%

Maternal vgll4a regulates zebrafish epiboly through Yap1 activity

Camacho-Macorra,

Tabanera,

Sánchez-Bustamante

et al. 2024

Front. Cell Dev. Biol.

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Gastrulation in zebrafish embryos commences with the morphogenetic rearrangement of blastodermal cells, which undergo a coordinated spreading from the animal pole to wrap around the egg at the vegetal pole. This rearrangement, known as epiboly, relies on the orchestrated activity of maternal transcripts present in the egg, compensating for the gradual activation of the zygotic genome. Epiboly involves the mechano-transducer activity of yap1 but what are the regulators of yap1 activity and whether these are maternally or zygotically derived remain elusive. Our study reveals the crucial role of maternal vgll4a, a proposed Yap1 competitor, during zebrafish epiboly. In embryos lacking maternal/zygotic vgll4a (MZvgll4a), the progression of epiboly and blastopore closure is delayed. This delay is associated with the ruffled appearance of the sliding epithelial cells, decreased expression of yap1-downstream targets and transient impairment of the actomyosin ring at the syncytial layer. Our study also shows that, rather than competing with yap1, vgll4a modulates the levels of the E-cadherin/β-catenin adhesion complex at the blastomeres’ plasma membrane and hence their actin cortex distribution. Taking these results together, we propose that maternal vgll4a acts at epiboly initiation upstream of yap1 and the E-cadherin/β-catenin adhesion complex, contributing to a proper balance between tissue tension/cohesion and contractility, thereby promoting a timely epiboly progression.

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Depletion of VGLL4 Causes Perinatal Lethality without Affecting Myocardial Development

Cited by 6 publications

References 39 publications

The puzzling case of the 3p25 homozygous deletion: the target is notVHLbutVGLL4andATG7

The puzzling case of the 3p25 homozygous deletion: the target is notVHLbutVGLL4andATG7

Vestigial like 4 regulates the adipogenesis of classical brown adipose tissue

Maternal vgll4a regulates zebrafish epiboly through Yap1 activity

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