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Wnt signaling in spermatogenesis and male infertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Vertika Singh, Meghali Joshi, Kiran Singh, Rajender Singh
Frizzled receptors like GPCRs are seven-transmembrane proteins acting as the primary receptors for Wnt signaling. The Fz receptor consists of an extracellular cysteine-rich domain (CRD), which is the site of interaction with Wnt proteins (22). There are 10 FZD genes present in humans, numbered from FZD1 to FZD10. FZD proteins are divided into five subgroups: FZD1/2/7, FZD3/6, FZD5/8, FZD9/10 and FZD4 (23). Another family of receptors is called low-density lipoprotein-related receptors (LRPs), which are single-pass transmembrane proteins and are over 1,600 amino acids in size (24,25). LRP5 and LRP6 are the homologs of Drosophila Arrow protein (26). They are also important for signal transduction along with FZD receptors. This raised the possibility that FZD and LRP function as coreceptors for Wnt proteins. An interaction between Wnt and LRP has been seen, and a ternary complex is formed between Wnt and extracellular domains of FZD and LRP in mouse (25). It has been reported that the overexpression of the intracellular domain of LRP6 can activate the Wnt signaling constitutively, suggesting that the extracellular domain plays a regulatory role in controlling signal transduction. There are multiple phosphorylation sites present on the intracellular domain of LRP5/6. The phosphorylation of these sites is important for the initiation of the signal transduction through Wnt/β-catenin signaling. LRP6 is phosphorylated by many kinases either in a Wnt-dependent (G protein receptor kinase 5/6) or Wnt-independent (protein kinase A, PFTAIRE protein kinase 1) manner (27).
Expression Levels of WNT Signaling Pathway Genes During Early Tooth Development
Published in Organogenesis, 2023
Yuhan Song, Fujie Song, Xuan Xiao, Zhifeng Song, Shangfeng Liu
Fzd10 is one of the FZD family receptors which act through canonical Wnt signaling.42 Fzd10regulates cell proliferation and mediates Wnt1-induced neurogenesis in the developing spinal cord.71 Investigations have demonstrated that mutations in the gene of Prkaca result in the development of adrenocortical adenomas associated with Cushing’s syndrome.72 Fzd7 plays a significant role in the regulation of multipotentiality of human pluripotent stem cells and its down-regulation accompanies differentiation and exit from the pluripotent stem cell state Dkk2 plays an important role in ovarian cancer.73,74 It has been well documented that Cer1 plays dual roles in neural induction and suppression of mesodermal or endodermal lineages.40 We observed that the mRNA expression levels of Fzd10 and Prkaca were mainly high during bud stage (E14.5), Fzd7 and Dkk2 were mainly highly expressed during cap stage (E16.5), and Cer1 was high during early bell stage (E18.5), indicating that they may play important roles in the early stage of tooth germ development. The expression level of Ctnnnbip1 was mainly high during P1 stage (late bell stage), enlightening that Ctnnbipmay be related to the formation and mineralization of enamel and dentin. Compared to the embryonic stages, the mRNA expression levels of Wnt3a and Dkk3 were highly expressed during postnatal stages, which implied that once significant high expression of Wnt3a and Dkk3 were found, it indicated that tooth germ has developed to the stage of hard tissue formation and mineralization. By contrary, Wnt16 was expressed only during E14.5 and E16.5, suggesting that Wnt16 was one of the important markers of early development of tooth germ.
Dishevelled 1, a pivotal positive regulator of the Wnt signalling pathway, mediates 5-fluorouracil resistance in HepG2 cells
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Yisong Xu, Cheng Zhang, Hui Liang, Shanshuang Hu, Pengkun Li, Linna Liu, Xianglong Duan, Chao Chen, Yani Zhang, Penggao Dai
In this work, we primarily reported an association between the Wnt signalling pathway and 5-FU resistance in HCC. We found that the expression of seven key genes in the Wnt signalling pathway was significantly altered in the 5-FU-resistant cells, of which FZD10 and DVL1 were upregulated and DKK1, DKK3, ZNRF3, RNF43 and APC2 were downregulated. We also found that the expression of β-catenin was upregulated in the 5-FU-resistant cells. Interestingly, the proteins of these genes are intrinsically associated with each other in the Wnt signalling process. DKK1, DKK3, ZNRF3 and RNF43 are upstream inhibitors of the Wnt signalling pathway and prevent the formation of active Wnt-Frizzled-LRP5/6 receptor complexes [22,33]. Recently, a complex interaction between these negative regulators and miRNAs was discovered where some miRNAs repressed target mRNAs in the Wnt signalling pathway. Lu et al. [27] found that miR-100 and miR-125b co-ordinately downregulated five negative regulators (DKK1, DKK3, ZNRF3, RNF43 and APC2) of the canonical Wnt/β-catenin signalling pathway, leading to increased Wnt signalling during de novo synthesis and acquired cetuximab resistance in CRC and head and neck squamous cell cancer (HNSCC) cell lines. In turn, activation of these receptor complexes, including FZD10, resulted in the activation of dishevelled proteins such as DVL1, inhibition of glycogen synthase kinase 3 beta, nuclear accumulation of β-catenin, and activation of the Wnt target genes. According to our current understanding of the Wnt signalling pathway, we posited a regulation model in 5-FU-resistant cancer cells where DKK1, DKK3, ZNRF3, RNF43 and APC2 expressions were downregulated, resulting in the overexpression of downstream FZD10 (also known as frizzled homologue 10 (Drosophila)) and DVL1, thereby mediating 5-FU resistance via the Wnt signalling pathway in HepG2/5-FU cells (Figure 6). In the current study, our transcriptome sequencing results support this model exactly, indicating that regulation of the Wnt signalling pathway is a key factor in acquiring 5-FU resistance in HCC. However, we need to employ more strategies to verify if these regulatory mechanisms exist in HepG2/5-FU cells.