Dickkopf-related protein 4 (DKK4) is a member of the dickkopf family and an inhibitor of the Wnt/β -catenin signalling pathway [2]. The Wnt signal pathway is involved in embryonic development, homeostasis maintenance and tumor pathogenesis [1]. DKK4 is associated with multiple biological processes such as tumour growth, invasion, migration, chemotherapy resistance, osteoblastogenesis, and secondary hair or meibomian gland formation [2].

In a Dkk4 -Cre knock -in mouse line, Dkk4 -Cre activity was evident at the prospective sites of ectodermal appendages, overlapping with Dkk4 mRNA expression. Unexpectedly, a predominantly mesenchymal cell population in the embryo posterior also showed Dkk4 -Cre activity, and lineage-tracing suggested these cells were likely derived from a few Dkk4 -Cre-expressing cells in the epiblast at early gastrulation. Analyses of Dkk4 -Cre-expressing cells in developing hair follicle epithelial placodes revealed cellular heterogeneity [5].

In cancer research, DKK4 expression varies in different tumours. In colorectal cancer (CRC), DKK4 is elevated and inhibits cell metastasis by a novel negative feedback mechanism of the Wnt3a/DKK4/AKT/s552 β -catenin regulatory axis [3]. However, DKK4 enhances the resistance of CRC cells to 5-fluorouracil (5-Fu) and YN968D1 treatment [6]. In non-small cell lung cancer, DKK4-knockdown promotes the cytotoxic and pro-apoptotic activity of A549/DTX cells, suggesting its role in docetaxel resistance [4].

In conclusion, DKK4 is a crucial modulator of the Wnt/β -catenin pathway, playing diverse roles in ectodermal appendage development and cancer-related processes. The Dkk4 -Cre knock -in mouse model provides insights into its function in early mouse development and ectodermal appendage morphogenesis. In cancer, understanding DKK4's role in metastasis and chemotherapy resistance may offer potential therapeutic strategies.