Genetic regulation of developmental clocks

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Why do humans have a nine-month gestation period and mice have a three-week gestation period? It makes sense that more time is required to create a larger body mass, but how the timing of developmental events coordinates with species-specific differences in growth is largely unknown. Remarkably, the in vitro differentiation rate of pluripotent stem cells (PSCs) recapitulates species-specific developmental timing in vivo. Thus, many differentiation protocols using primate PSCs may require several months or sometimes years to complete, reflecting a longer gestation period. On the other hand, murine PSCs complete the same events in vitro in just days or weeks, reflecting a three-week gestation period. These observations suggest that even without normal developmental cues from intact embryonic and extraembryonic components, an intrinsic development timing/clock mechanism exists in cells. Therefore, a comparative analysis using an in vitro differentiation paradigm will help understand and characterize the fundamental mechanisms regulating developmental timing. The long-term goal of my research program is to determine the mechanisms regulating developmental timing, understand developmental clocks, and identify the factors that can modify the clock tempo. We recently established in vitro segmentation clock models using PSC-derived mesoderm progenitors, recapitulating species-specific gene oscillatory periodicity in vivo. Thus, our overarching hypothesis is that species-specific genetic factors play a central role in regulating developmental timing. Equipped with our novel in vitro developmental clock systems, this Discovery Grant application specifically aims to: 1) determine the tunable factors in the NOTCH signaling pathway that regulate the synchronization and periodicity of the segmentation clock; 2) determine if extrinsic or intrinsic factors could regulate species-specific clock periodicity; and 3) identify the links between the segmentation clock and HOX clock. The completion of these aims will not only shed light on the molecular mechanisms controlling a developmental clock during vertebrae development, but also provide a road map to understand how cells and tissues cooperate to make essential body plans. A basic understanding of developmental timing may ultimately lead to methods to accelerate the duration of in vitro differentiation and decouple it from in vivo gestation length. Notably, because developmental timing, body size, metabolic rate, and life span are all interconnected, understanding what controls timing during embryogenesis may offer new insights into what controls tissue regeneration and the aging processes.