Shaping of a simple organ by anisotropic biomechanical forces the diverse, elaborate but highly replicable forms of animal organs are critical for their functions. Organ forms are generated by a limited set of morphogenetic movements that ultimately involve mechanical forces, driven by and responsive to major influences such as cell-cell and cell-extracellular matrix (ECM) interactions. Our understanding of how these coordinately translate into a force balance that shapes a tissue in vivo is currently primitive. In particular, while recent work has revealed much about how cadherin-mediated cortical tension can regulate polarized cell behaviors, how forces created by organized ECMs in living animals drive organ morphogenesis remains poorly understood. The long-term goal of this work is to understand how the genome orchestrates mechanical forces that are integrated within a tissue to drive a specific three-dimensional shape. We will investigate this question in a simple organ, the Drosophila egg chamber, which undergoes an elemental developmental transition from an isotropic shape to elongate 2.5-fold along a single axis. Tissue elongation is a broadly conserved and critical event in many developing animal organs, and importantly, Drosophila egg elongation involves cell-cell and cell- matrix interactions. It also involves a collective cell migration that builds a distinctive polarized ECM. The Drosophila egg chamber thus lies at a 'sweet spot' with sufficient complexity to capture major vertebrate organ morphogenetic processes but sufficient simplicity and manipulability to elucidate general paradigms. The specific objective of this proposal is to determine how anisotropic forces generated by the ECM sculpt the growing egg chamber. We hypothesize that tissue rotation builds a planar-polarized ECM with distinct mechanical properties, and directs polarized cell rearrangements by anisotropically altering cell-cell interactions. We will test this hypothesis by combining the genetic manipulability of Drosophila with advanced imaging techniques and recently established biomechanical assays to measure and manipulate the forces involved. 4D imaging accompanied by quantitative computational analysis, laser severing and force-sensing biomechanical probes will measure tissue tension and ECM rigidity. Analysis of mutant and manipulated tissues that fail to elongate will reveal causal mechanisms generating protein and mechanical anisotropy, including the role of cell migration. The mechanisms uncovered will inform our understanding of human developmental defects and other diseases arising from altered mechanics of morphogenesis.
The elaborate shapes of the organs that support our lives are ultimately created by multiple mechanical forces. We are just starting to understand how genes and molecules generate these forces within cells, yet not even for the simplest organ do we understand how they coordinate in a living animal to sculpt a particular three- dimensional shape. The proposed research will study a simple and highly manipulable animal organ with new biomechanical, imaging, and genetic tools to reveal a paradigm for how changes in the force balance integrate to drive an elemental morphogenetic change.
|Kim, Jung; Bilder, David; Neufeld, Thomas P (2018) Mechanical stress regulates insulin sensitivity through integrin-dependent control of insulin receptor localization. Genes Dev 32:156-164|
|Bilder, David; Irvine, Kenneth D (2017) Taking Stock of the Drosophila Research Ecosystem. Genetics 206:1227-1236|
|Chen, Dong-Yuan; Crest, Justin; Bilder, David (2017) A Cell Migration Tracking Tool Supports Coupling of Tissue Rotation to Elongation. Cell Rep 21:559-569|
|Crest, Justin; Diz-Muñoz, Alba; Chen, Dong-Yuan et al. (2017) Organ sculpting by patterned extracellular matrix stiffness. Elife 6:|
|Bilder, David (2016) The Maturation of Development. Dev Cell 38:569-70|