While the mechanisms of embryonic development are well conserved, the progression speed differs among animal species. The molecular cause of ‘allochrony’, interspecies differences in developmental tempo, remains unclear due to lack of an appropriate experimental model. In vitro differentiation of pluripotent stem cells (PSCs) offers unique opportunities to compare the same cell type among diverse species in a similar condition.
We have previously recapitulated the oscillatory gene expression of the segmentation clock with PSCs, demonstrating ~2 hour and ~5 hour oscillation periods in murine and human induced presomitic mesoderm (PSM) cells, respectively. We have further found that the period difference stems from differential biochemical reaction speeds of HES7, a core segmentation clock gene, between the species: human PSM cells show slower degradation rates of HES7 and longer delays in its production processes than mouse cells.
Here we aim to investigate the deeper origin of developmental allochrony, the molecular mechanism by which human cells exhibit slower biochemical reactions. We will systematically and quantitatively measure the degradation rates and delays to reveal commonalities of the genes that show differential reaction speeds between murine and human cells (Aim 1). In parallel, we will test two working hypotheses that nuclear/cytoplasmic transport rates or metabolic rates might be lower in human cells, which should lead to slower biochemical reactions (Aim 2).
The other objective is to test the universality of the mechanism of allochrony. We will create gastruloids, organoids mimicking early embryogenesis, from PSCs of diverse mammalian species to investigate what cell types, in addition to PSM cells, and what species exhibit the differential biochemical reaction speeds (Aim 3).
This study will tackle a fundamental question in biology by using quantitative, cutting-edge technologies, ultimately enabling manipulation of developmental time.
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