Molecular and metabolic pathways controlling developmental timing. TempoReg

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A long-held question in biology is how developmental timing operates at the cellular level. Despite the similarities in the developmental programs between mammalian species, the pace (tempo) at which the developmental programs function is species-specific. Further, some species can halt development for extended periods of time in response to adverse nutrient conditions (diapause).Cell-intrinsic differences in timing between species can be recapitulated in vitro, and comparative stem cell models between species have pioneered the identification of tempo mechanisms. My work identified that the rate at which proteins are dismantled corresponds to developmental tempo, with reduced protein degradation rates associated with slower tempo. However, the consequences of modulating protein turnover remain to be tested, and the mechanisms upstream of developmental tempo remain to be identified. Understanding how tempo is modulated will help us understand how changes in the pace of development may lead to changes of size and why timing is a source of evolutionary change.TempoReg aims to develop a holistic understanding of the molecular and metabolic pathways that control tempo by combining genome-wide dynamic proteomic, metabolic and transcriptomic measurements with pharmacological and genetic perturbations, with the ultimate goal of identifying mechanisms to modulate developmental pace. Specifically, TempoReg will address the following questions: (1) what is the role of protein turnover in developmental tempo? (2) how is tempo controlled by metabolic mechanisms?, and (3) can we modulate developmental tempo within a species?As well as shedding light on a fundamental question with implications across molecular, cell, organismal, and evolutionary scales, this project also has broad practical applications. Changing the pace of developmental processes may reduce the timescales for the production of human specific cell types from embryonic stem cells employed for research or for therapeutic applications in the clinic.