PATTERN AND GROWTH · Coordination of patterning and growth in the developing neural tube

Developing organs are patterned as they grow, but it is poorly understood how patterning and growth are coordinated to produce tissues of correct final proportions. In the vertebrate nervous system, neuronal type specification occurs in parallel with progenitor proliferation and differentiation. In the ventral neural tube, a Sonic hedgehog (Shh) morphogen gradient organizes the pattern of neuronal progenitors, and also influences their proliferation. How these two processes are coordinated and whether Shh provides the link between patterning and growth is poorly understood. This is in part due to the lack of high-resolution quantitative data that captures the dynamic changes in proliferation, specification and Shh signaling in neural cells. To address this issue, I will first perform high-resolution spatiotemporal lineage tracing, as well as in vivo analyses in combination with molecular markers for cell fate and cell cycle progression. These data will be used to build a mathematical model that captures the types and rates of division specific to distinct cell types, positions and times. With this framework, I will quantitatively analyze conditions where growth, pattern or Shh signaling are affected to test the logic of how these are coordinated in mouse and chick. Finally, I will examine in vivo, using Shh activity reporters, how signaling at the single cell level is converted to specific proliferation and specification responses. Together, this project provides a novel opportunity to understand the fundamental principles that govern tissue pattern and growth. In addition, it may also have implications for understanding disease states in which growth and cellular differentiation are disrupted.