Generative model for the first cell fate bifurcation in mammalian development.

Area of Science:

• Developmental Biology
• Cell Biology
• Systems Biology

Background:

• The initial cell fate decision in mammalian embryos distinguishes trophectoderm (TE) and inner cell mass (ICM) lineages.
• This critical bifurcation is regulated by the YAP transcriptional co-activator's subcellular localization during asynchronous cell divisions.
• Analyzing TE/ICM specification dynamics in fixed embryos is challenging due to blastomere asynchrony and arrangement.

Purpose of the Study:

• To develop and apply a live-imaging approach for quantifying cell fate dynamics in early mammalian development.
• To construct a generative model of the first cell fate bifurcation using YAP, CDX2, and SOX2 dynamics.
• To investigate the stochasticity and temporal heterogeneity in TE/ICM cell allocation and its developmental significance.

Main Methods:

• Live imaging of pre-implantation embryos to track nuclear YAP localization and expression of target genes CDX2 (TE marker) and SOX2 (ICM marker).
• Measurement of pairwise dynamics of YAP, CDX2, and SOX2.
• Development of a generative model to analyze TE/ICM cell allocation statistics and YAP dynamics.

Main Results:

• The generative model accurately predicts time-dependent statistics of TE/ICM cell allocation.
• The model reveals the stochastic timing of key cell fate determinant induction (CDX2 and SOX2).
• Temporal heterogeneity in SOX2 expression within the ICM was prominent, potentially influencing subsequent developmental decisions.

Conclusions:

• The study elucidates the dynamic regulation of the first cell fate decision in mammalian development.
• The developed live-imaging and modeling approach provides a framework for dissecting cell fate choices.
• Understanding ICM cell heterogeneity is crucial for investigating subsequent developmental events.