Thursday, April 3, 2025
4/3/2025
Nonautonomous control of substrate morphogenesis by migrating cells - PROJECT SUMMARY/ABSTRACT Collective cell migration is essential for the precise assembly of many tissues and organs during development, and involves the interplay between multiple cell types. In all modes of collective migration, interactions with a substrate modulate parameters such as cell polarity, directional movement, and even growth and morphogenesis, with the extracellular matrix (ECM) serving as a scaffold for various signaling cues for migratory cohorts. However, the extent to which migrating cells exert a reciprocal influence on their substrate remains largely unknown. Drosophila caudal visceral mesoderm (CVM) cells undergo synchronous bilateral collective migration along a trunk visceral mesoderm (TVM) substrate, which expresses fibroblast growth factor (FGF) ligands that serve as chemoattractive, survival, and growth cues in order to drive proper CVM migration and quality control to pattern the larval midgut musculature. However, CVM cells also display an unprecedented level of influence on TVM development, with mismigrating CVM cells altering the directional growth habit of TVM cells. The objective of this proposal is to understand the mechanistic basis for this interaction between the CVM and TVM. We hypothesize that CVM cells nonautonomously modulate directional growth in the TVM through positive regulation of the bone morphogenetic protein (BMP) signaling pathway. We will employ a hybrid approach of established immunostaining and live imaging techniques to assay the respective potential contributions of the BMP and FGF signaling pathways through tissue-specific rescue and loss-of-function experiments. The rationale behind this approach is that understanding the mechanism underlying interdependent tissue interactions will allow us to uncover novel ways in which precursor cells interact with their extracellular environment during collective migration. The objective will be accomplished via two specific aims: 1) Investigate the role of BMP signaling in CVM-dependent morphogenesis of the TVM, and 2) optimize in vivo live imaging to elucidate the nature of CVM-TVM interactions over the course of migration. Our working hypothesis is that tissue-specific regulation of the BMP signaling repressor brinker (brk) by the CVM is required to modulate TVM growth prior to myoblast fusion. As the majority of research has focused on identifying and characterizing the signaling cues that tissue substrates use to modulate the behavior of migrating cells, this work is innovative in that it investigates a dramatic, previously unknown example of how migrating cells can in turn influence their substrate beyond modifying the extracellular matrix (ECM). This work is significant in that it will contribute to a long-term research program for studying how multiple, complex interactions between different tissues allow for proper patterning of an organ, which is of interest to cell, developmental, and cancer biologists, as evidence for nonautonomous effects on tissue substrates has implications for increasing our understanding of the mechanisms responsible for tumor metastases.
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