Project Summary/Abstract The broad goal of the proposed research is to understand molecular mechanisms of tooth regeneration and tissue renewal in vertebrates. Our research benefits from explicit integration of experimental systems (cichlid fishes, zebrafish, mouse) and a unique approach translating new biology from fishes to mammals and back. In this competitive renewal application, we build on the previous project period to outline three Specific Aims that fuse unbiased and experimental approaches in multiple vertebrate tooth models to identify cell populations and molecular signals that direct natural whole-tooth replacement (cichlids and zebrafish) and mouse incisor tissue renewal. The gaps we aim to fill are significant. One in five humans presents with a genetic disorder affecting the dentition and nearly 100% develop problems (e.g, cavities) with age. 30% of people worldwide over the age of 65 lack teeth entirely. Our proposed research will provide answers to the basic question of how regenerating teeth are partitioned into coordinated zones of renewal and differentiation, and how mammalian teeth recover from damage. Insights should promote innovative strategies for bio-inspired regenerative dentistry.