Mechanical Clocks During Fetal Development

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PROJECT SUMMARY Development is all about timing. From fertilized egg to newborn infant, embryonic development proceeds as a highly coordinated sequence of stereotyped events. The order and timing of each stage of the process, including the timing of tissue morphogenesis and differentiation of progenitor cells, are essential for building mature organs in time for birth. Defects in timing are associated with both congenital birth defects as well as chronic diseases in the adult, including asthma, emphysema, renal failure, and type II diabetes. What controls the tempo of development – the central metronome of the embryo – is one of the great mysteries of biology. Only a handful of molecular timers have been discovered to-date, including the circadian and segmentation clocks, both of which operate as transcriptional oscillators that are entrained by periodic activation of extracellular biochemical stimuli. However, it is unclear how biochemical signals that are transmitted by diffusion can couple the rates of development of organs that are separated by large distances within the embryo. We recently discovered unexpectedly that the rate of morphogenesis of the embryonic mammalian lung is entrained by mechanical forces from luminal fluid pressure, which controls the frequency of synchronized epithelial branching and smooth muscle contraction across the organ. These findings suggest the presence of a “mechanical clock” in the fetus. Because fluid pressure is transmitted instantaneously between distant tissues, a mechanical clock could synchronize the rates of development across organs, permitting coordinated maturation before birth. Here, we propose to investigate the coupling of lung, kidney, and pancreatic development, organs that are all connected by fluid within and around the embryo and that form via branching morphogenesis. We will define how the magnitude of pressure controls the rates of proliferation, differentiation, and morphogenesis using microfluidics approaches. We will also identify the oscillatory signaling pathways that are induced by pressure and investigate how fluid forces are transmitted between distant organs to ensure that their rates of development are coupled. We will combine organ-on-a-chip models, tissue-specific reporter animals, transgenic knockout mice, single-cell transcriptomics and proteomics, and quantitative time-lapse imaging analysis, and complement these with studies of human patient samples and mouse models of entrainment defects. This work will uncover how the shared mechanical environment of fetal organs permits them to grow and mature coordinately in time for birth, which is essential for designing new approaches to treat disorders associated with congenital defects and developmental prematurity, as well as chronic diseases in the adult.