Integrative Analysis of Cell Communication and Morphogenesis in a Multicellular System

Morphogenesis is a complex process that involves the integration of individual behaviors of thousands of cells throughout time and space. To elucidate the process is to understanding communications between the cells. The mechanisms of communication include receptors that transduce information from extracellular to intracellular environment and second messengers that carry the information via their dynamics to inform cell decision-making. However, the complexity of the system poses a major challenge in efficient dissecting the mechanisms of cellular and tissue communication. Therefore, an integrative approach is needed for the investigating and the analysis of the communication in multicellular systems.

In this dissertation, I used Drosophila melanogaster—a classic model organism—to investigate cellular and tissue communication based on calcium (Ca2+) and G protein-coupled receptors (GPCRs), in the context of wound healing and tissue development. I reviewed the most up-to-date advances of technology that is used to reverse-engineer multicellular systems (Chapter 1). With these tools, I conducted detailed analysis of Ca2+ dynamics in wounded and developing tissues (Chapter 2 and 3). The analysis revealed that mechanical anisotropy within the tissue impact the Ca2+ flash propagation after wounding (Chapter 2). It also demonstrated that Ca2+ dynamics reversely correlate with progression of tissue development, potentially serving as a

signal to coordinate collective behaviors of cells within a developing tissue (Chapter 3). The implicate of Ca2+ in tissue development led to the investigation of the roles of GPCRs, a group of upstream regulators of Ca2+ dynamics, during epithelial development (Chapter 4). We demonstrated the power of neural networks in handling bio-images and the efficiency of statistical models in analyzing complex structures of data. Interestingly, many neuropeptide and neurotransmitter receptors, which previously were not known to have functions in morphogenesis, were shown to regulate Drosophila wing development. The finding demonstrated the connection between nervous-system-related GPCRs and epithelial development. In addition, Drosophila brain was used as a drug-discovery platform for Down syndrome (Chapter 5). The Drosophila platform was tightly integrated with drug synthesis process that accelerates the iteration of drug development and the advancement of drugs onto next-stage mouse models. Finally, future trends in how the advance in analytical tools will propel the study of cell communication and morphogenesis are discussed in the concluding chapter (Chapter 6).