Wnt/Notum spatial feedback inhibition controls neoblast differentiation to regulate reversible growth of the planarian brain

Mechanisms determining final organ size are poorly understood. Animals undergoing regeneration or ongoing adult growth likely require sustained and robust mechanisms to achieve and maintain appropriate sizes. Planarians, well known for their ability to undergo whole-body regeneration due to pluripotent adult stem cells of the neoblast population, can reversibly scale body-size over an order of magnitude by controlling cell number. Using quantitative analysis, we show that after injury planarians perfectly restore brain:body proportion by increasing brain cell number through epimorphosis or decreasing brain cell number through tissue remodeling (morphallaxis), as appropriate. We identify a pathway controlling a brain size set-point that involves feedback inhibition between wnt11-6/wntA/wnt4a and notum, encoding conserved antagonistic signaling factors expressed at opposite brain poles. wnt11-6/wntA/wnt4a undergoes feedback inhibition through canonical Wnt signaling but likely regulates brain size in a non-canonical pathway independently of beta-catenin-1 and APC. Wnt/Notum signaling tunes numbers of differentiated brain cells in regenerative growth and tissue remodeling by influencing the abundance of brain progenitors descended from pluripotent stem cells, as opposed to regulating cell death. These results suggest that the attainment of final organ size might be accomplished by achieving a balance of positional signaling inputs that regulate the rates of tissue production.