Mechanisms of Crosstalk and Signal Integration of Calcium Signaling in Epithelial Tissues

Organogenesis relies on complex and dynamic cellular processes that are mediated by genetic programs, governed by extrinsic and intrinsic signals, and are extensively coordinated through intercellular communication. During organ development, patterned gene expressions and biochemical signals regulate growth, proliferation, and mechanics to build complex tissues through tissue-level processing. Specific unit operations of tissue shaping include epithelial spreading, folding, and sculpting. These processes are essential for shaping two-dimensional epithelial sheets into complex three-dimensional structures. In addition, these morphogenetic modules are regulated throughout the development of an organism, from gastrulation to organogenesis. Dysregulation of these morphogenetic processes leads to various diseases, including congenital disabilities and cancer. However, the precise mechanisms through which the gene expression patterns regulate the coordinated cellular processes during organogenesis are poorly understood. A quantitative, mechanistic understanding of the biophysical mechanisms regulating the cellular processes is essential to understand the design principles regulating morphogenesis. These design principles would help develop effective therapeutics to repair defects during embryonic development and wound healing. Additionally, a systems-level understanding of combining multiple morphogenesis modules can guide advanced methods for regenerating tissues from basic building blocks.

In this dissertation, Drosophila melanogaster is used as a model system to investigate how critical biochemical signals coordinate collective cellular processes to drive epithelial morphogenesis. Epithelial tissues transduce key biochemical signals into specific cellular responses through second messenger dynamics such as calcium. Hence, it is crucial to understand how epithelial cells interpret diverse signals and transduce them into second messengers, such as calcium, to coordinate tissue-level processes. Calcium is one of the crucial second messengers regulating various physiological processes and is essential for regulating a diverse range of cellular functions such as growth, mechanics, apoptosis, and proliferation. Additionally, calcium signaling is also associated with a physiological signaling system, and its role in regulating neuronal and other physiological activity is well established. However, the mechanisms through which global patterning information integrates second messenger dynamics to regulate the key morphogenetic operations still need to be fully elucidated. Moreover, decoding the calcium signaling and its crosstalk with other signaling cascades during epithelial morphogenesis is highly relevant to wound healing and cancer. This is due to the high similarity of cell signaling pathways across the animal kingdom and the cross-hierarchical nature of biological systems. In fact, it is often possible to establish and leverage phenotypic analogies between genetic perturbations in a (slightly) simpler animal like the fruit fly and human diseases to identify promising drug targets and drug candidate systems.

This dissertation discusses studies investigating the mechanisms that integrate calcium signaling in regulating epithelial morphogenesis during development. A key motivation for this work is the long-term goal of inferring cell/tissue/organ states from dynamic measurements of a few ‘hubs’ within cell signaling networks that can capture a large percentage of the whole information processing network within cell systems. Such an integrated knowledge base contributes to defining over-arching design principles of organ development and homeostasis.