PUBLICATION
A conserved Notch-Meis1-Pbx cascade specifies secretory progenitors into spatially diverse intestinal best4+ cells
- Authors
- Sur, A., Segal, E.X., Nunneley, M.P., Sinclair, J.W., Prochaska, M.K., Dye, L.E., Wu, Y., Fu, L., Shi, Y.B., Iben, J., Feldman, B., Farrell, J.A.
- ID
- ZDB-PUB-260808-11
- Date
- 2026
- Source
- Genes & Development : (Journal)
- Registered Authors
- Farrell, Jeffrey, Feldman, Benjamin
- Keywords
- ATOH1, MEIS1, Notch, PBX3, best4+ cells, developmental biology, intestine, pH response, secretory progenitors, zebrafish
- Datasets
- GEO:GSE329135
- MeSH Terms
- none
- PubMed
- 42567676 Full text @ Genes & Dev.
Citation
Sur, A., Segal, E.X., Nunneley, M.P., Sinclair, J.W., Prochaska, M.K., Dye, L.E., Wu, Y., Fu, L., Shi, Y.B., Iben, J., Feldman, B., Farrell, J.A. (2026) A conserved Notch-Meis1-Pbx cascade specifies secretory progenitors into spatially diverse intestinal best4+ cells. Genes & Development. :.
Abstract
best4+ cells are a recently described vertebrate intestinal epithelial cell type. best4+ cells are altered in inflammatory bowel disease and colorectal cancer, suggesting that stimulation of their homeostatic replenishment may have therapeutic potential. However, the development and function of best4+ cells remain unclear. Since mice lack best4+ cells, 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 conserved in best4+ cells across vertebrates. Lineage tracing demonstrated that best4+ cells arise from secretory progenitors, where Notch/Dll4 signaling mediates a decision between best4+ and enterochromaffin cells by triggering meis1b expression. Following specification by meis1b, pbx3a spatially diversifies best4+ cells, which develop regional heterogeneity in gene expression, intracellular pH, and function. In vivo live imaging and removal of best4+ cells showed that best4+ cells sense luminal pH changes and extend dynamic luminal and stromal projections, but are not required to restore global luminal pH after challenge. Altogether, this study experimentally delineates best4+ cell developmental regulation and develops a genetic toolkit to examine their function in vivo, both of which will aid investigating how best4+ cells are altered or can be restored during disease.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping