Dishevelled-DEP domain interacting protein (DDIP) inhibits Wnt signaling by promoting TCF4 degradation and disrupting the TCF4/β-catenin complex

The TCF4/β-catenin complex, the executor of canonical Wnt/β-catenin signaling, is regulated by a variety of factors. Among these, Dishevelled (Dvl) is a critical regulator that releases β-catenin from degradation and stabilizes TCF4/β-catenin complex. Here, we report that DDIP (Dishevelled-DEP domain Interacting Protein, also named as Spats1, spermatogenesis associated, serine-rich 1), a novel protein that interacts with Dvl, regulates Wnt signaling. We provide evidence that DDIP suppresses Lef-1 luciferase reporter activity stimulated by Wnt1, Dvl2 or β-catenin, interacts with the TCF4/β-catenin complex, and disrupts the interaction of TCF4 and β-catenin by promoting TCF4 degradation through the proteasome pathway. Our results indicate that DDIP is a negative regulator of the canonical Wnt signaling.     

Eif2s3y regulates the proliferation of spermatogonial stem cells via Wnt6/-catenin signaling pathway

Eukaryotic translation initiation factor 2 subunit 3 and structural gene Y-linked (Eif2s3y) gene, the gene encoding eIF2γ protein, is globally expressed in all tissues and plays important roles in regulating global and gene-specific mRNA translation initiation. It has been noticed that Eif2s3y plays crucial roles in spermatogenesis, however, the mechanism remains unclear. In the current study, transgenic Eif2s3y mice were generated to test our hypothesis that the Eif2s3y promotes the proliferation of spermatogonial stem cells (SSCs). Transgenic Eif2s3y mouse had enhanced SSCs proliferation rate when compared to WT mouse. Interesting, the testes from transgenic Eif2s3y mouse had increased Active-β-catenin protein expression and higher expression pattern of Wnt ligand Wnt6 when compared to testes from WT mouse. This study revealed novel roles of Eif2s3y in the activation Wnt6/β-catenin signal pathway in SSCs. Taken together, we identified Eif2s3y-Wnt6-β-catenin as a critical pathway in the regulation of spermatogenesis, which provides a platform for investigating the molecular mechanisms of male reproduction.