Spatiotemporal modeling reveals cellular regulatory dynamics driving tissue and organ development

Abstract

Understanding how cellular behaviors give rise to tissue- and organ-scale morphology is a central challenge in developmental biology. The multiscale nature of development makes it difficult to experimentally determine which interactions are responsible for observed developmental outcomes. This dissertation uses computational modeling to investigate these questions, with a primary focus on neural stem cell lineages in the developing Drosophila brain. Chapter 1 reviews recent spatiotemporal multiscale modeling studies across developmental biology, gynecological pathology, and cellular senescence, and introduces a framework for categorizing models according to the biological scales at which dynamics are imposed and outcomes emerge. Chapter 2 develops ordinary differential equation models of neural stem cell growth, division, and differentiation to evaluate candidate regulatory mechanisms capable of constraining mutant stem cell lineage expansion. Chapter 3 develops a spatially explicit Cellular Potts model to investigate how spatially regulated growth and division behaviors shape lineage morphology during brain development. Across these studies, computational models are used as tools for identifying the minimal cellular-scale mechanisms sufficient to generate observed developmental phenotypes. Together, this work demonstrates how computational modeling can be used to investigate multiscale developmental systems and generate hypotheses linking cellular interactions to tissue-scale outcomes.