An RNAi Screen Reveals Intestinal Regulators of Branching Morphogenesis, Differentiation, and Stem Cell Proliferation in Planarians

Planarians grow and regenerate organs by coordinating proliferation and differentiation of pluripotent stem cells with remodeling of postmitotic tissues. Understanding how these processes are orchestrated requires characterizing cell-type-specific gene expression programs and their regulation during regeneration and homeostasis. To this end, we analyzed the expression profile of planarian intestinal phagocytes, cells responsible for digestion and nutrient storage/distribution. Utilizing RNA interference, we identified cytoskeletal regulators required for intestinal branching morphogenesis and a modulator of bioactive sphingolipid metabolism, ceramide synthase, required for the production of functional phagocytes. Additionally, we found that a gut-enriched homeobox transcription factor, nkx-2.2, is required for somatic stem cell proliferation, suggesting a niche-like role for phagocytes. Identification of evolutionarily conserved regulators of intestinal branching, differentiation, and stem cell dynamics demonstrates the utility of the planarian digestive system as a model for elucidating the mechanisms controlling postembryonic organogenesis. Organ regeneration coordinates stem cell proliferation and differentiation with remodeling of postmitotic tissues. Forsthoefel et al. purify planarian intestinal cells, characterize their expression profile, and perform a targeted RNAi screen. Their work on transcription factor Nkx2.2 suggests that intestinal phagocytes play a niche-like role to maintain neighboring pluripotent stem cells.