Wnt signalling in testicular descent: A candidate mechanism for cryptorchidism in Robinow syndrome

Harisis, George; Chen, Nan; Farmer, Pamela J.; Bodemer, Daniela; Li, Ruili; Sourial, Magdy; Southwell, Bridget R.; Balic, Adam; Hutson, John M.

doi:10.1016/j.jpedsurg.2012.08.038

Cited by 13 publications

(9 citation statements)

References 22 publications

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“…The germ line c-Cbl mutations have developmental and functional consequences (28). Hyperactive Wnt signaling has been implicated in several of those conditions (29,30), which now can be linked through the present data. Overall, the c-Cbl-Wnt-␤-catenin relationship has implications both in angiogenesis and tumorigenesis.…”

Section: Discussionsupporting

confidence: 59%

The c-Cbl Ubiquitin Ligase Regulates Nuclear β-Catenin and Angiogenesis by Its Tyrosine Phosphorylation Mediated through the Wnt Signaling Pathway

Shivanna¹,

Harrold²,

Shashar³

et al. 2015

Journal of Biological Chemistry

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Background: ␤-Catenin is an important mediator of angiogenesis; however, its molecular regulation is poorly understood. Results: Wnt promotes phosphorylation of c-Cbl on Tyr-731, enhancing its dimerization and nuclear translocation to degrade nuclear ␤-catenin. Conclusion: Wnt-mediated c-Cbl phosphorylation regulates nuclear ␤-catenin. Significance: Targeting c-Cbl E3 ligase activity could destabilize ␤-catenin and inhibit pathological angiogenesis.

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Section: Discussionsupporting

confidence: 59%

The c-Cbl Ubiquitin Ligase Regulates Nuclear β-Catenin and Angiogenesis by Its Tyrosine Phosphorylation Mediated through the Wnt Signaling Pathway

Shivanna¹,

Harrold²,

Shashar³

et al. 2015

Journal of Biological Chemistry

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“…The importance of Wnt signaling in mouse embryonic and postnatal development and in diseases has been reported by several authors [5,12,20e22]. Activation of Wnt signaling has been revealed as the underlying etiology of some cryptorchidisms [9]. AXIN1, the wild-type AXIN gene, a negative regulator of this pathway, has been suggested to play an important role during embryogenesis.…”

Section: Discussionmentioning

confidence: 98%

The variations in the AXIN1 gene and susceptibility to cryptorchidism

Zhou

Tang

Chen

et al. 2015

Journal of Pediatric Urology

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“…Knockout experiments in mice clearly show independent requirements for INSL3/RXFP2 and androgens in testicular descent ( 16 , 17 ); nevertheless causative mutations in INSL3, RXFP2, AR (androgen receptor) or the Leydig cell regulator NR5A1 (steroidogenic factor-1), are rare in cases of cryptorchidism ( 18 , 19 ). WNT signaling appears to be a downstream target of both INSL3 and androgen in the fetal rat gubernaculum ( 20 , 21 ), and cryptorchidism and/or gubernacular maldevelopment occur in mice with transgenic deletion of WNT pathway genes, such as Sfrp1/Sfrp2, Wnt5a, Ctnnb , or Vangl2 ( 16 , 22 – 25 ). Yet none of these genes has been implicated in human cryptorchidism.…”

Section: Leydig Cell Hormones Work Separately and Together To Bring Amentioning

confidence: 99%

Perspective: A Neuro-Hormonal Systems Approach to Understanding the Complexity of Cryptorchidism Susceptibility

Barthold

Ivell

2018

Front. Endocrinol.

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Nonsyndromic cryptorchidism is a common multifactorial, condition with long-term risks of subfertility and testicular cancer. Revealing the causes of cryptorchidism will likely improve prediction and prevention of adverse outcomes. Herein we provide our current perspective of cryptorchidism complexity in a synthesis of cumulative clinical and translational data generated by ourselves and others. From our recent comparison of genome-wide association study (GWAS) data of cryptorchidism with or without testicular germ cell tumor, we identified RBFOX family genes as candidate susceptibility loci. Notably, RBFOX proteins regulate production of calcitonin gene-related peptide (CGRP), a sensory neuropeptide linked to testicular descent in animal models. We also re-analyzed existing fetal testis transcriptome data from a rat model of inherited cryptorchidism (the LE/orl strain) for enrichment of Leydig cell progenitor genes. The majority are coordinately downregulated, consistent with known reduced testicular testosterone levels in the LE/orl fetus, and similarly suppressed in the gubernaculum. Using qRT-PCR, we found dysregulation of dorsal root ganglia (DRG) sensory transcripts ipsilateral to undescended testes. These data suggest that LE/orl cryptorchidism is associated with altered signaling in possibly related cell types in the testis and gubernaculum as well as DRG. Complementary rat and human studies thus lead us to propose a multi-level, integrated neuro-hormonal model of testicular descent. Variants in genes encoding RBFOX family proteins and/or their transcriptional targets combined with environmental exposures may disrupt this complex pathway to enhance cryptorchidism susceptibility. We believe that a systems approach is necessary to provide further insight into the causes and consequences of cryptorchidism.

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Wnt signalling in testicular descent: A candidate mechanism for cryptorchidism in Robinow syndrome

Cited by 13 publications

References 22 publications

The c-Cbl Ubiquitin Ligase Regulates Nuclear β-Catenin and Angiogenesis by Its Tyrosine Phosphorylation Mediated through the Wnt Signaling Pathway

The c-Cbl Ubiquitin Ligase Regulates Nuclear β-Catenin and Angiogenesis by Its Tyrosine Phosphorylation Mediated through the Wnt Signaling Pathway

The variations in the AXIN1 gene and susceptibility to cryptorchidism

Perspective: A Neuro-Hormonal Systems Approach to Understanding the Complexity of Cryptorchidism Susceptibility

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