DESCRIPTION: The sizes of tissues and organs are specified with great precision, a fact we notice in the symmetry of bilateral structures (such as limbs), and the degree to which genetically identical individuals resemble each other. Not only do tissues and organs reach specific sizes, they do so in the face of cell killing or alterations to cell cycle kinetics, which suggests a feedback control mechanism. Work from our group on continually- renewing tissues has identified a general "integral negative feedback" strategy, whereby negative regulation of stem or progenitor cell renewal automatically achieves robust set-point control. Such feedback may be conveyed by diffusible growth factors-as we and others showed in the olfactory epithelium (OE), retina, and muscle-but a variety of molecules and mechanisms could act similarly. Regardless of mechanism, however, the ability of local feedback to control proliferation is subject to distance limitations: molecular and mechanical signals decay over characteristic length scales. The fact that such scales are often very short-on the order of 100 µm or less-raises questions about how local feedback could possibly control the sizes of tissues and organs that are three or four orders of magnitude larger. Here we address this issue through a combination of mathematical modeling and animal experimentation. Preliminary modeling has identified several strategies that could, in principle, enable large sizes to be controlled through short-range feedback. These strategies exploit the fact that controlling developmental tissue and organ growth is not a "steady-state" problem, but one of controlling a self-terminating trajectory. By considering a variety of possible cell lineage relationships and types of feedback interactions-all of which are motivated by observations in actual developing systems-we will use modeling and simulation to systematically discover the design principles out of which strategies for feedback control of large tissues and organs may be constructed. Subsequently, we will computationally test the hypothesis that the best way to distinguish experimentally among different potential growth-control strategies is by transiently ablating defined proportions of cells at specific lineage stages, and observing the consequences for final tissue size. Finally, we will perform just such transient cell ablations to investigate the development of three neural structures-the olfactory epithelium, the neural retina, and the cerebral neocortex-in mice, with the goal of identifying the strategies these tissues use for size control in different dimensions. This work will provide both basic insights into fundamental processes of development, and specific insights into size control in the nervous system. The results will be of direct relevance o the etiology of microcephaly and other birth defects, as well as to clinical phenomena of stunting, catch-up growth, and growth-asymmetry.

PUBLIC HEALTH RELEVANCE: Size control is one of the oldest and most fascinating problems in biology. The work proposed here will exploit both mathematical modeling and experimental manipulation of genetically engineered mice to discover how the sizes of tissues and organs are precisely specified in the face of developmental variability and external perturbations. The results will be directly relevant to the understanding of normal human variation; the origins of birth defects and growth-asymmetry; and the mechanisms underlying "catch-up" growth following malnutrition, infection or injury.