Project description
It’s all about timing: the paradigm of embryonic development
Embryonic development begins after fertilisation and undergoes the same stages in many species, at however different paces depending on the organism. The underlying aetiology of the differences in developmental time between species remains unclear. The working hypothesis of the EU-funded ALLOCHRONY project is that this developmental allochrony is due to different rates in key biochemical reactions. Researchers will develop organoids from pluripotent stem cells that mimic early embryogenesis to study key reactions in mouse and human cells. Results will advance existing knowledge on embryonic development and identify the rate-limiting steps in the process.
Objective
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.
Fields of science
Programme(s)
Funding Scheme
ERC-COG - Consolidator GrantHost institution
01069 Dresden
Germany