We focus on distinct cellular structures that mediate cell adhesion and contractility. Cell-matrix and cell-cell junctions and the actomyosin cytoskeleton are responsible for the dynamic control of cell and tissue shape during development and homeostasis and their mis-regulation is associated with various diseases.Collaborating with experts in single molecule imaging, mass-spectrometry, and bioinformatics, and specializing ourselves in genetics and live-cell imaging, we are taking a multi-scale approach – from single proteins to a whole organism – to address the following mechanobiological questions:
Regulation of actomyosin contractility
Contractile tubes are a hallmark of many important animal organs, such as blood and lymphatic vessels, lung airways, mammary and salivary glands, and urinal and reproductive tracts. In larger tubular tissues, contractility is afforded by smooth muscle cells surrounding epithelial cells, and in smaller tubes the epithelial or endothelial cells themselves are contractile. Misregulation of contractility, and hence of tube diameter, is responsible for several human diseases, such as hypertension and asthma. Mechanical cues, sensed by cell adhesion sites and the cytoskeleton, play an important role in regulating cellular contractility.
Actomyosin cytoskeleton in fibroblasts
The actomyosin network is essential for cellular functions such as migration and adhesion, where force generation and sensing are important properties. Parallel actomyosin stress fibers crosslinked by a-actinin can additionally be crosslinked by highly structured arrays of myosin, called myosin stacks, that form when myosin regions in neighboring stress fibers align with each other [Hu et al., 2017]. In a recent study we could additionally show that this specific order of the cytoskeleton plays a role in the capacity of cells to generate forces [Hu, Grobe et al., 2019].
Cytoskeleton dynamics in embryogenesis
Embryogenesis comprises of serial, and on occasion simultaneous, occurrence of highly coordinated and regulated processes that lead to the formation of an organism. These processes are fairly conserved in all animal embryos. During embryogenesis, morphogenetic changes take place to bring about the formation of tissues from an initial mass of cells. Morphogenesis relies on individual and collective cell changes in shape, neighborhood or identity to drive the generation and folding of individual tissues and organs to allow their functionality. Extensive research has focused on the mechanisms that orchestrate morphogenesis, yet much remains unexplored.
All multicellular organisms embrace an intricate set of organs with unique architecture and functionality. Organogenesis, i.e. formation of an organ, involves a coordination of biochemical signals and mechanical cues. Although a significant advancement has been made in understanding the genetic regulation of different cell and tissue behaviors during 3D organ development, the role of mechanical force is only beginning to emerge. We use Caenorhabditis elegans reproductive organ, i.e. gonad as a model, to explore the physical basis of organ development.
Modeling of human disease in C. elegans
The decreasing cost of whole genome sequencing and the push toward personalized medicine is driving an exponential growth in the number of human patients who have their genomes sequenced. As a result, more than 80 million variations in the genome, including single nucleotide polymorphisms, insertions, deletions, and other structural variants have been identified. The challenge is thus twofold: first, to identify which human genetic variations cause disease, and second, to elucidate how, at the molecular and cellular level, the genetic changes cause the diseases. The goal of this project is to generate human disease-associated genetic variations in the orthologous genes of C. elegans.