A conserved Notch-Meis1-Pbx cascade specifies secretory progenitors into spatially diverse intestinal best4+ cells

ABSTRACT: best4+ cells are a recently described vertebrate intestinal epithelial cell type. best4+ cells are reduced in inflammatory bowel disease and transcriptionally altered in colorectal cancer, suggesting that stimulation of their homeostatic replenishment may have therapeutic potential. However, it is unclear what function best4+ cells perform or how they develop, which is crucial to understand to therapeutically manipulate them. Since best4+ cells are evolutionarily lost in mice, here we established zebrafish as a tractable in vivo model to observe, manipulate, and remove best4+ cells in an organismal context. We dissected best4+ cell developmental regulation in vivo from birth to differentiation and specialization, focusing on factors that we show are evolutionarily conserved in best4+ cells across vertebrates. We demonstrate with lineage tracing that best4+ cells arise from secretory progenitors, where Notch/Dll4 signaling mediates a decision between best4+ and enterochromaffin cells by triggering expression of meis1b. Following specification by meis1b, we identify a role for pbx3a in the spatial diversification of best4+ cells, which develop regional heterogeneity in gene expression and intracellular pH that implies potential functional specialization. Together, in vivo live imaging, in vivo removal of best4+ cells, and non-autonomous effects on goblet cells suggest these cells have a sensory or communicative function. Altogether, this study experimentally delineates a comprehensive best4+ cell developmental program and develops a genetic toolkit to dissect their function in vivo, both of which will be instrumental to understand how best4+ cells are altered in disease and to stimulate the birth of new best4+ cells in patients.

ORGANISM(S): Danio rerio

PROVIDER: GSE329135 | GEO | 2026/05/05

REPOSITORIES: GEO