Multi-scale feedbacks for robust organ development

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PROJECT SUMMARY One of the hallmarks of successful embryonic development is the reproducible and robust formation of organs with the right shape and size. Failures in organ morphogenesis can result in developmental disorders, lifelong birth defects, and, in some cases, embryonic lethality and miscarriage. To address how complex forms reproducibly arise from simple tissues, research studies across species have provided a simple mechanistic framework, where genetic-information patterns cellular mechanics to drive tissue morphogenesis. However, this simple framework, where information flows hierarchically from genes to cells to tissues, fails to account for: (i) biological noise causing variations in tissue patterns, (ii) multi-scale feedback interactions, and (iii) guiding roles of tissue geometry. To address these outstanding challenges in organ morphogenesis, we will utilize an exemplary organ common to all vertebrate organisms— the semicircular canals of the inner ear, in an accessible genetic model system— the zebrafish. The three canals are mutually orthogonal, and this precise angular architecture is required for detecting head rotations and maintaining balance. The intricate morphology of the canals arises from the topological remodeling of a simple embryonic tissue, making it one of the most geometrically complex and accurate morphogenic processes amenable to study. To investigate how canal morphogenesis achieves robustness, we will establish a new experimental paradigm by leveraging high-resolution microscopy, single-cell transcriptomic data, statistical analysis, genetic, physical, and biophysical perturbations, and predictive physical modelling. This paradigm will be deployed to: (i) measure variations in tissue patterns and morphologies; (ii) add variations to tissue patterns for dissecting out the respective contributions of genetically-encoded instructions versus other regulatory mechanisms, and (iii) systematically investigate the physical constraints from tissue geometry and feedbacks through mechano-transduction in “canalizing” variations during development. These innovative, distinct yet complementary approaches will deliver a new, integrative framework encapsulating reciprocal flow of information between genetic-patterns, cell behaviors and tissue geometry for successful embryonic development. This framework will be used to identify the etiology of developmental defects and disorders in vivo. By revealing underlying causes for birth defects or miscarriages, our research may, in the long term, also impact human healthcare.