Original WB Images Deng et. al. Developmental Cell 2024

The homeostasis of the intestinal epithelium relies on intricate yet insufficiently understood mechanisms of intestinal epithelial plasticity. Here, we elucidate the pivotal role of Frizzled5 (Fzd5), a Wnt pathway receptor, as a murine intestinal epithelial cell fate determinant. Fzd5 deletion in Lgr5+ intestinal stem cells (ISCs) impairs their self-renewal capacity and disrupts the lineage-tracing ability of Krt19+ cells without affecting crypt integrity. However, a broader deletion of Fzd5 across the epithelium leads to crypt deterioration. Integrated analysis of Single-cell RNA sequencing (ScRNA-seq) and single-cell ATAC-seq (ScATAC-seq) identifies that Fzd5 governs chromatin accessibility, orchestrating the regulation of stem and lineage-related gene expression mainly in ISCs and progenitor cells. In summary, our findings provide insights into the regulatory role of Fzd5 in governing intestinal epithelial plasticity.