Katoh Y and Katoh M, Int J Mol Med 2005 Mar;15(3):527-31.
WNT and Hedgehog signaling pathways are implicated in various types of human cancer, such as gastric and pancreatic cancer. WNT1, WNT2, WNT2B (WNT13), WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A (WNT14), WNT9B (WNT14B). WNT10A, WNT10
B, WNT11 and WNT16 genes encode WNT family glycoproteins, which transduce signals through Frizzled (FZD) family receptors with extracellular WNT-binding and cytoplasmic Dishevelled-binding domains. WNT6 and WNT10A genes at human chromosome 2q35 are clustered in tail-to-head manner with an interval of <7 kb. Here, we identified and characterized rat Wnt6 and Wnt10a genes by using bioinformatics. Wnt6 and Wnt10a genes were clustered in tail-to-head manner with an interval of about 7 kb within AC127107.3 and AC132020.3 genome sequences. Rat Wnt6 gene, consisting of four exons, encoded a 365-aa protein with signal peptide, 24 conserved Cys residues, two Asn-linked glycosylation sites and an RGD motif. Rat Wnt10a gene, consisting of four exons, encoded a 417-aa protein with 24 conserved Cys residues, two Asn-linked glycosylation sites and an RGD motif. Rat Wnt6 and human WNT6 showed 97.8% total-amino-acid identity, while rat Wnt10a and human WNT10A showed 95.4% total-amino-acid identity. Promoter region was conserved between rat Wnt6 and human WNT6 genes. GATA, FOXA2, and TGIF binding sites were located within the conserved region of rat Wnt6 and human WNT6 promoters. This is the first report on rat Wnt6 and Wnt10a genes as well as on the conserved promoter region of Wnt6 orthologs.
Wnt signaling has recently emerged as an important regulator of cardiac progenitor cell proliferation and differentiation, but the exact mechanisms by which Wnt signaling modulates these effects are not known. Understanding these mechanisms is essential for advancing our knowledge of cardiac progeni
tor cell biology and applying this knowledge to enhance cardiac therapy. Here, we explored the effects of Sfrp2, a canonical Wnt inhibitor, in adult cardiac progenitor cell (CPC) differentiation and investigated the molecular mechanisms involved. Our data show that Sfrp2 treatment can promote differentiation of CPCs after ischemia-reperfusion injury. Treatment of CPCs with Sfrp2 inhibited CPC proliferation and primed them for cardiac differentiation. Sfrp2 binding to Wnt6 and inhibition of Wnt6 canonical pathway was essential for the inhibition of CPC proliferation. This inhibition of Wnt6 canonical signaling by Sfrp2 was important for activation of the non-canonical Wnt/Planar Cell Polarity (PCP) pathway through JNK, which in turn induced expression of cardiac transcription factors and CPC differentiation. Taken together, these results demonstrate a novel role of Sfrp2 and Wnt6 in regulating the dynamic process of CPC proliferation and differentiation, as well as providing new insights into the mechanisms of Wnt signaling in cardiac differentiation.
Li R, etal., J Endod. 2014 Jul;40(7):943-8. doi: 10.1016/j.joen.2013.12.023. Epub 2014 Feb 13.
INTRODUCTION: During the dental pulp repair process, human dental pulp cells (HDPCs) migrate to injury sites where they may differentiate into odontoblastlike cells. WNT6 plays a role in dental development and can activate a noncanonical pathway including the c-
Jun N-terminal kinase (JNK) pathway. The mechanism of WNT6 in dental pulp repair is still unknown. The purpose of this study was to explore the potential role of the WNT6/JNK signaling pathway in the promotion of cell migration and the differentiation of HDPCs. METHODS: The third passage of HDPCs were cultured in vitro and treated with WNT6 conditioned medium with or without the pretreatment of JNK inhibitor SP600125. The activation of JNK was detected by Western blot, the expression of c-Jun was quantified by reverse-transcription polymerase chain reaction, the migration of HDPCs was determined by wound healing and transwell migration assays, and the differentiation of HDPCs was investigated using alkaline phosphatase staining and alizarin red staining. The expression of odontogenesis-related genes such as Runt-related transcription factor 2, dentin sialophosphoprotein, and dentin matrix protein 1 was quantified. RESULTS: WNT6 activates the JNK pathway in HDPCs and enhances cell migration, mineralization nodule formation, and alkaline phosphatase activation. WNT6 also increases the expression of Runt-related transcription factor 2, dentin sialophosphoprotein, and dentin matrix protein messenger RNA in HDPCs. Blockage of the JNK pathway in HDPCs decreases but does not completely abolish the cell migration and differentiation capacity induced by WNT6. CONCLUSIONS: WNT6 activates the JNK signaling pathway in HDPCs, leading to migration and differentiation.
