A fundamental question in developmental biology concerns the origin and control of patterns and shapes, also known as morphogenesis. Multicellular signaling networks, encoded in genetic networks, underlie the normal development of embryos and drive their morphogenesis. Paradigmatic example is the periodic segmentation of mesoderm into somites, the precursors of the vertebrae, during vertebrate development. Changes in genes, effector proteins, and cellular environments can lead to altered embryonic development as seen in congenital disorders. To cure diseases we need to understand how genes control cells at multiple scales and how groups of cells form coherent, functional tissues and organs. The last years have witnessed a boom in discoveries in developmental biology with single-cell sequencing, microfluidics, optics, increased computational power leading to unprecedented spatiotemporal resolution of the multiscale dynamics of morphogenetic systems, from molecules to cells to whole embryos. While these advancements have produced detailed roadmaps of the events orchestrated during develop- ment, we still lack a clear picture of which cellular networks drive collective morphogenetic programs. The classical forward and reverse genetic perturbative screenings, and even modern perturbative tools like optogenetics, still mainly focus at the level of the gene(s) or single signaling pathways. This makes it challenging to infer causal relationship between complex multicellular networks and developmental transitions. New perturbative tools are needed that could construct similar complexity as the ones observed in vivo. As these complex networks in vivo are based on cell-cell and cell-environment communication pathways, we need controllable versions of those pathways that we can (i) link in complex synthetic networks, (ii) use to control endogenous developmental pathways. Such a system would enable the introduction of precise and complex spatiotemporal perturbations at the level of the networks instead of the gene(s), ultimately delivering increased understanding of the relationship between complex networks and resulting developmental transitions. In our lab we develop synthetic cell-cell and cell-ECM pathways, connect them in networks, and use them to investigate developmental processes. Here we propose to (i) use these tools to investigate the mechanistic contribution of Notch signaling to the formation and propagation of signaling waves in the presomitic mesoderm and, (ii) develop new tools for cell-ECM communication, inspired by developmental signaling. We expect to enter a cycle of toolstestanswersnew questionsnew tools. These studies will advance the field of developmental biology by shedding light on the behavior and logic of multicellular systems and how complex networks enable control across scales of space and time. Gaining insight and tools to direct developmental cell populations would have widespread relevance for the treatment of developmental defects and our capacity to control the growth of tissue and organs in a dish.

Public Health Relevance

Signaling networks, encoded in genetic networks, underlie the normal development of embryos and can cause developmental abnormalities when disrupted. To cure diseases, we need to understand how genes control signaling networks at multiple scales, and how these networks drive cells to form coherent functional tissues and organs through the process of morphogenesis; this is not simple, as these signaling networks are complex and perturbations at the molecular level propagate in a very complex way to the embryo level. We propose to study how complex genetic and cellular signaling networks function by developing computational and biological models mimicking their behavior, and by probing natural systems with higher-order perturbative tools, hoping to understand their function and logic from subsequent changes at the morphogenetic level.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Unknown (R35)
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Special Emphasis Panel (ZRG1)
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Brazhnik, Paul
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University of Southern California
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
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